Our Publications

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Azetidines Kill Multidrug-Resistant Mycobacterium tuberculosis without Detectable Resistance by Blocking Mycolate Assembly

Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC99 values <10 μM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies.

Yixin Cui, Alice Lanne, Xudan Peng, Edward Browne, Apoorva Bhatt, Nicholas J. Coltman, Philip Craven, Liam R. Cox, Nicholas J. Cundy, Katie Dale, Antonio Feula, Jon Frampton, Martin Fung, Michael Morton, Aaron Goff, Mariwan Salih, Xingfen Lang, Xingjian Li, Chris Moon, Jordan Pascoe, Vanessa Portman, Cara Press, Timothy Schulz-Utermoehl, Suki Lee, Micky D. Tortorella, Zhengchao Tu, Zoe E. Underwood, Changwei Wang, Akina Yoshizawa, Tianyu Zhang, Simon J. Waddell, Joanna Bacon, Luke Alderwick, John S. Fossey, and Cleopatra Neagoie Journal of Medicinal Chemistry. Published online.Linkopen
Data science in drug discovery safety: Challenges and opportunities

Early de-risking of drug targets and chemistry is essential to provide drug projects with the best chance of success. Target safety assessments (TSAs) use target biology, gene and protein expression data, genetic information from humans and animals, and competitor compound intelligence to understand the potential safety risks associated with modulating a drug target. However, there is a vast amount of information, updated daily that must be considered for each TSA. We have developed a data science–based approach that allows acquisition of relevant evidence for an optimal TSA. This is built on expert-led conventional and artificial intelligence–based mining of literature and other bioinformatics databases. Potential safety risks are identified according to an evidence framework, adjusted to the degree of target novelty. Expert knowledge is necessary to interpret the evidence and to take account of the nuances of drug safety, the modality, and the intended patient population for each TSA within each project. Overall, TSAs take full advantage of the most recent developments in data science and can be used within drug projects to identify and mitigate risks, helping with informed decision-making and resource management. These approaches should be used in the earliest stages of a drug project to guide decisions such as target selection, discovery chemistry options, in vitro assay choice, and end points for investigative in vivo studies.

Coltman NJ, Roberts RA, Sidaway JE. Data science in drug discovery safety: Challenges and opportunities. Experimental Biology and Medicine. 2023;248(21):1993-2000LinkOpen
Glycolysis: An early marker for vancomycin-specific T-cell activation

Vancomycin, a glycopeptide antibiotic used for Gram-positive bacterial infections, has been linked with drug reaction with eosinophilia and systemic symptoms (DRESS) in HLA-A*32:01-expressing individuals. This is associated with activation of T lymphocytes, for which glycolysis has been isolated as a fuel pathway following antigenic stimulation. However, the metabolic processes that underpin drug-reactive T-cell activation are currently undefined and may shed light on the energetic conditions needed for the elicitation of drug hypersensitivity or tolerogenic pathways. Here, we sought to characterise the immunological and metabolic pathways involved in drug-specific T-cell activation within the context of DRESS pathogenesis using vancomycin as model compound and drug-reactive T-cell clones (TCCs) generated from healthy donors and vancomycin-hypersensitive patients.

Gardner J, Hammond S, Jensen R, et al. Glycolysis: An early marker for vancomycin-specific T-cell activation. Clin Exp Allergy. 2024; 54: 21-33LinkOpen
An integrated approach for early in vitro seizure prediction utilizing hiPSC neurons and human ion channel assays

Seizure liability remains a significant cause of attrition throughout drug development. Advances in stem cell biology coupled with an increased understanding of the role of ion channels in seizure offer an opportunity for a new paradigm in screening. We assessed the activity of 15 pro-seizurogenic compounds (7 CNS active therapies, 4 GABA receptor antagonists, and 4 other reported seizurogenic compounds) using automated electrophysiology against a panel of 14 ion channels (Nav1.1, Nav1.2, Nav1.6, Kv7.2/7.3, Kv7.3/7.5, Kv1.1, Kv4.2, KCa4.1, Kv2.1, Kv3.1, KCa1.1, GABA α1β2γ2, nicotinic α4β2, NMDA 1/2A). These were selected based on linkage to seizure in genetic/pharmacological studies. Fourteen compounds demonstrated at least one “hit” against the seizure panel and 11 compounds inhibited 2 or more ion channels. Next, we assessed the impact of the 15 compounds on electrical signaling using human-induced pluripotent stem cell neurons in microelectrode array (MEA). The CNS active therapies (amoxapine, bupropion, chlorpromazine, clozapine, diphenhydramine, paroxetine, quetiapine) all caused characteristic changes to electrical activity in key parameters indicative of seizure such as network burst frequency and duration. The GABA antagonist picrotoxin increased all parameters, but the antibiotics amoxicillin and enoxacin only showed minimal changes. Acetaminophen, included as a negative control, caused no changes in any of the parameters assessed. Overall, pro-seizurogenic compounds showed a distinct fingerprint in the ion channel/MEA panel. These studies highlight the potential utility of an integrated in vitro approach for early seizure prediction to provide mechanistic information and to support optimal drug design in early development, saving time and resources.

Rockley K, Roberts R, Jennings H, Jones K, Davis M, Levesque P, Morton M. An integrated approach for early in vitro seizure prediction utilizing hiPSC neurons and human ion channel assays. Toxicol Sci. 2023 Oct 30;196(1):126-140LinkOpen
DeepAmes: A deep learning-powered Ames test predictive model with potential for regulatory application

The Ames assay is required by the regulatory agencies worldwide to assess the mutagenic potential risk of consumer products. As well as this in vitro assay, in silico approaches have been widely used to predict Ames test results as outlined in the International Council for Harmonization (ICH) guidelines. Building on this in silico approach, here we describe DeepAmes, a high performance and robust model developed with a novel deep learning (DL) approach for potential utility in regulatory science. DeepAmes was developed with a large and consistent Ames dataset (>10,000 compounds) and was compared with other five standard Machine Learning (ML) methods. Using a test set of 1,543 compounds, DeepAmes was the best performer in predicting the outcome of Ames assay. In addition, DeepAmes yielded the best and most stable performance up to when compounds were >30% outside of the applicability domain (AD). Regarding the potential for regulatory application, a revised version of DeepAmes with a much-improved sensitivity of 0.87 from 0.47. In conclusion, DeepAmes provides a DL-powered Ames test predictive model for predicting the results of Ames tests; with its defined AD and clear context of use, DeepAmes has potential for utility in regulatory application.

Ting Li, Zhichao Liu, Shraddha Thakkar, Ruth Roberts, Weida Tong, DeepAmes: A deep learning-powered Ames test predictive model with potential for regulatory application, Regulatory Toxicology and Pharmacology, Volume 144, 2023, 105486LinkOpen
Structure-activity relationship of dihydropyridines for rhabdomyosarcoma

Childhood muscle-related cancer rhabdomyosarcoma is a rare disease with a 50-year unmet clinical need for the patients presented with advanced disease. The rarity of ∼350 cases per year in North America generally diminishes the viability of large-scale, pharmaceutical industry driven drug development efforts for rhabdomyosarcoma. In this study, we performed a large-scale screen of 640,000 compounds to identify the dihydropyridine (DHP) class of anti-hypertensives as a priority compound hit. A structure-activity relationship was uncovered with increasing cell growth inhibition as side chain length increases at the ortho and para positions of the parent DHP molecule. Growth inhibition was consistent across n = 21 rhabdomyosarcoma cell line models. Anti-tumor activity in vitro was paralleled by studies in vivo. The unexpected finding was that the action of DHPs appears to be other than on the DHP receptor (i.e., L-type voltage-gated calcium channel). These findings provide the basis of a medicinal chemistry program to develop dihydropyridine derivatives that retain anti-rhabdomyosarcoma activity without anti-hypertensive effects.

Shefali Chauhan, Andrew D. Woods, Narendra Bharathy, Xiaolei Lian, Cora A. Ricker, Amy Mantz, William J. Zuercher, Lisa H. Price, Michael J. Morton, Eric Durrant, Stéphane Y. Corbel, Srinath C. Sampath, Srihari C. Sampath, John Joslin, Charles Keller, Structure-activity relationship of dihydropyridines for rhabdomyosarcoma, Biochemical and Biophysical Research Communications, Volume 667, 2023, Pages 138-145LinkRestricted Access
What’s been Hapten-ing over the last 88 years?

Definition of the relationship between drug protein adduct formation (haptenation) and development of immunological adverse drug reactions (drug hypersensitivity) has been an area of active research for over 80 years. The hapten hypothesis which states that “immunogenicity of low molecular weight organic chemicals is dependent on modification of self-proteins,” evolved from Landsteiner and Jacob’s discovery of a correlation between the reactivity of dinitro-halogenated benzenes and their sensitization potential. The hypothesis rapidly evolved to encompass drugs that often require metabolic activation to generate electrophilic, protein-reactive intermediates. As tissue culture methods advanced, the importance of drug hapten-specific T-cells in the disease pathogenesis was defined. This led to a plethora of studies describing the uptake and processing of drug(metabolite) protein adducts by antigen presenting cells, and the subsequent surface display of hapten-modified peptides in the context of MHC molecules. Although the pathway of hapten-specific T-cell activation is now well established, several questions need to be addressed: first, what is the nature of the hapten-modified peptides displayed by MHC? Second, how many of these peptides stimulate T-cells?; third, what are the critical protein modifications involved in T-cell activation; and finally, what is the role of hapten-specific T-cells in the iatrogenic disease? These questions will become increasingly important as more and more targeted covalent binding inhibitor drugs are approved for human use. In this review, we provide a brief synopsis of hapten research and then describe the approaches used by Pharma and academia to study hapten covalent binding and the role of drug protein adducts in the activation of human T-cells.

Thomson, P., Hammond, S., Meng, X. et al. What’s been Hapten-ing over the last 88 years?. Med Chem Res 32, 1950–1971 (2023)LinkOpen
Characterization of Drug-Specific CD4+ T‑Cells Reveals Possible Roles of HLA Class II in the Pathogenesis of Carbamazepine Hypersensitivity Reactions

Carbamazepine (CBZ) is an aromatic anticonvulsant known to cause drug hypersensitivity reactions, which range in severity from relatively mild maculopapular exanthema to potentially fatal Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN). These reactions are known to be associated with human leukocyte antigen (HLA) class I alleles, and CBZ interacts preferentially with the related HLA proteins to activate CD8+ T-cells. This study aimed to evaluate the contribution of HLA class II in the effector mechanism(s) of CBZ hypersensitivity. CBZ-specific T-cells clones were generated from two healthy donors and two hypersensitive patients with high-risk HLA class I markers. Phenotype, function, HLA allele restriction, response pathways, and cross-reactivity of CBZ-specific T-cells were assessed using flow cytometry, proliferation analysis, enzyme-linked immunosorbent spot, and enzyme-linked immunosorbent assay. The association between HLA class II allele restriction and CBZ hypersensitivity was reviewed using Allele Frequency Net Database. Forty-four polyclonal CD4+ CBZ-specific T-cell clones were generated and found to be restricted to HLA-DR, particularly HLA-DRB1*07:01. This CD4+-mediated response proceeded through a direct pharmacological interaction between CBZ and HLA-DR molecules. Similar to the CD8+ response, CBZ-stimulated CD4+ clones secreted granulysin, a key mediator of SJS-TEN. Our database review revealed an association between HLA-DRB1*07:01 and CBZ-induced SJS-TEN. These findings implicate HLA class II antigen presentation as an additional pathogenic factor for CBZ hypersensitivity reactions. Both HLA class II molecules and drug-responsive CD4+ T-cells should be evaluated further to gain better insights into the pathogenesis of drug hypersensitivity reactions.

Jaruthamsophon K, Thomson PJ, Hammond S, Zhang E, Alfirevic A, Sukasem C, Naisbitt DJ, Pirmohamed M. Characterization of Drug-Specific CD4+ T-Cells Reveals Possible Roles of HLA Class II in the Pathogenesis of Carbamazepine Hypersensitivity Reactions. Chem Res Toxicol. 2023 May 15;36(5):757-768.LinkOpen
Artificial intelligence and real-world data for drug and food safety – A regulatory science perspective

In 2013, the Global Coalition for Regulatory Science Research (GCRSR) was established with members from over ten countries (www.gcrsr.net). One of the main objectives of GCRSR is to facilitate communication among global regulators on the rise of new technologies with regulatory applications through the annual conference Global Summit on Regulatory Science (GSRS). The 11th annual GSRS conference (GSRS21) focused on “Regulatory Sciences for Food/Drug Safety with Real-World Data (RWD) and Artificial Intelligence (AI).” The conference discussed current advancements in both AI and RWD approaches with a specific emphasis on how they impact regulatory sciences and how regulatory agencies across the globe are pursuing the adaptation and oversight of these technologies.

Shraddha Thakkar, William Slikker, Frank Yiannas, Primal Silva, Burton Blais, Kern Rei Chng, Zhichao Liu, Alok Adholeya, Francesco Pappalardo, Mônica da Luz Carvalho Soares, Patrick E. Beeler, Maurice Whelan, Ruth Roberts, Jurgen Borlak, Martha Hugas, Carlos Torrecilla-Salinas, Philippe Girard, Matthew C. Diamond, Didier Verloo, Binay Panda, Miquella C. Rose, Joaquim Berenguer Jornet, Ayako Furuhama, Hong Fang, Ernest Kwegyir-Afful, Kasey Heintz, Kirk Arvidson, Juan Garcia Burgos, Alexander Horst, Weida Tong, Regulatory Toxicology and Pharmacology, Volume 140, 2023LinkOpen
Detection of Hepatic Drug Metabolite-Specific T-Cell Responses Using a Human Hepatocyte, Immune Cell Coculture System

Drug-responsive T-cells are activated with the parent compound or metabolites, often via different pathways (pharmacological interaction and hapten). An obstacle to the investigation of drug hypersensitivity is the scarcity of reactive metabolites for functional studies and the absence of coculture systems to generate metabolites in situ. Thus, the aim of this study was to utilize dapsone metabolite-responsive T-cells from hypersensitive patients, alongside primary human hepatocytes to drive metabolite formation, and subsequent drug-specific T-cell responses.

Ali SE, Meng X, Kafu L, Hammond S, Zhao Q, Ogese M, Sison-Young R, Jones R, Chan B, Livoti L, Sun Y, Sun L, Liu H, Topping A, Goldring C, Zhang F, Naisbitt DJ. Chem Res Toxicol. 2023 Mar 20;36(3):390-401.LinkOpen
Science-led regulatory strategies in nonclinical development of new medicines

The development of a pharmaceutical is a stepwise process involving an evaluation of both animal and human efficacy and safety information. Regulations around drug development exist to protect people and the environment from harm and should create a level playing field for business, allowing well-run companies to thrive. However, adherence to good science should guide decisions rather than rigorously following guidelines, and there is almost always more than one way to get to the ultimate goal.

Ruth Roberts, David Jones, Toxicology Research, 2023LinkRestricted Access
Activation of tolvaptan-responsive T-cell clones with the structurally-related mozavaptan

Tolvaptan is an effective drug for the treatment of autosomal dominant polycystic kidney disease, but its use is associated with a significant risk of T-cell-mediated liver injury in a small number of patients.

Sean Hammond, Xiaoli Meng, Merrie Mosedale, Dean J. Naisbitt, Toxicology Letters, Volume 373, 2023, Pages 148-151LinkOpen
Pathology of drug hypersensitivity reactions and mechanisms of immune tolerance

Immune-mediated type IV adverse drug reactions are idiosyncratic in nature, generally not related to the primary or secondary pharmacology of the drug. Due to their complex nature and rarity, these iatrogenic reactions are seldom predicted or encountered during preclinical/early clinical development stages, and often precipitate upon exposure to wider populations (i.e. phase III onwards).

Thomson P, Hammond S, Naisbitt DJ. . Clin Exp Allergy. 2022 Dec; 52(12):1379-1390LinkRestricted Access
Fifty years of the BTS—some reflections

As we celebrate 50 years of the BTS, it is timely to consider what topics and challenges dominated our thinking in toxicology 50 years ago and how things have evolved to the current day.

Ruth Roberts, Kim Rockley, Emma Marczylo, Heather Wallace, Toxicology Research, Volume 11, Issue 5, October 2022, Pages 709–710,LinkOpen
Does immune checkpoint inhibitor therapy increase the frequency of adverse reactions to concomitant medications?

In recent years, the clinical installation of immune checkpoint inhibitors (ICIs) has proven to be an exceptionally valuable addition to
oncological therapy, illustrating superior short- and long-term efficacy in challenging-to-treat malignancies and taking on an increasing
role across the majority of disease sites.

Hammond S, Olsson-Brown A, Grice S, Naisbitt DJ. Clin Exp Allergy. 2022 May;52(5):600-603.LinkOpen
Tox-GAN: An Artificial Intelligence Approach Alternative to Animal Studies—A Case Study With Toxicogenomics

Animal studies are a critical component in biomedical research, pharmaceutical product development, and regulatory submissions. There is a worldwide effort in toxicology toward “reducing, refining, and replacing” animal use.

Xi Chen, Ruth Roberts, Weida Tong, Zhichao Liu, Toxicological Sciences, Volume 186, Issue 2, April 2022, Pages 242–259LinkRestricted Access
Checkpoint Inhibition Reduces the Threshold for Drug-Specific T-Cell Priming and Increases the Incidence of Sulfasalazine Hypersensitivity

An emerging clinical issue associated with immune-oncology agents is the collateral effects on the tolerability of concomitant medications. One report of this phenomenon was the increased incidence of hypersensitivity reactions observed in patients receiving concurrent immune checkpoint inhibitors (ICIs) and sulfasalazine (SLZ).

Sean Hammond, Anna Olsson-Brown, Sophie Grice, Andrew Gibson, Joshua Gardner, Jose Luis Castrejón-Flores, Carol Jolly, Benjamin Alexis Fisher, Neil Steven, Catherine Betts, Munir Pirmohamed, Xiaoli Meng, Dean John Naisbitt, Toxicological Sciences, Volume 186, Issue 1, March 2022, Pages 58–69,LinkOpen
Malarial PI4K inhibitor induced diaphragmatic hernias in rat: Potential link with mammalian kinase inhibition

MMV390048 is an aminopyridine plasmodial PI4K inhibitor, selected as a Plasmodium blood-stage schizonticide for a next generation of malaria treatments to overcome resistance to current therapies. MMV390048 showed an acceptable preclinical safety profile and progressed up to Phase 2a clinical trials. However, embryofetal studies revealed adverse developmental toxicity signals, including diaphragmatic hernias and cardiovascular malformations in rats but not rabbits.

Demarta-Gatsi, C., Donini, C., Duffy, J., Sadler, C., Stewart, J., Barber, J. A., & Tornesi, B. (2022) Birth Defects Research, 114(10), 487–498.LinkOpenN/A
T cell mediated hypersensitivity to previously tolerated iodinated contrast media precipitated by introduction of atezolizumab

Many adverse reactions associated with immune checkpoint inhibitor (ICI) treatments are immunologically driven and may necessitate discontinuation of the ICI. Herein, we present a patient who had been administered the radio contrast media amidotrizoate multiple times without issue but who then developed a Stevens-Johnson syndrome reaction after coadministration of atezolizumab.

Hammond S, Olsson-Brown A, Gardner J, et al; Journal for ImmunoTherapy of Cancer 2021;9LinkOpen
A target safety assessment of the potential toxicological risks of targeting plasmepsin IX/X for the treatment of malaria

The aspartic proteases plasmepsin IX/X are important antimalarial drug targets due to their specificity to the malaria parasite and their vital role as mediators of disease progression. Focusing on parasite-specific targets where no human homologue exists reduces the possibility of on-target drug toxicity. However, there is a risk of toxicity driven by inadequate selectivity for plasmepsins IX/X in Plasmodium over related mammalian aspartic proteases. Of these, CatD/E may be of most toxicological relevance as CatD is a ubiquitous lysosomal enzyme present in most cell types and CatE is found in the gut and in erythrocytes, the clinically significant site of malarial infection. Based on mammalian aspartic protease physiology and adverse drug reactions (ADRs) to FDA-approved human immunodeficiency virus (HIV) aspartic protease inhibitors, we predicted several potential toxicities including β-cell and congenital abnormalities, hypotension, hypopigmentation, hyperlipidaemia, increased infection risk and respiratory, renal, gastrointestinal, dermatological, and other epithelial tissue toxicities. These ADRs to the HIV treatments are likely to be a result of host aspartic protease inhibition due a lack of specificity for the HIV protease; plasmepsins are much more closely related to human CatD than to HIV proteinase. Plasmepsin IX/X inhibition presents an opportunity to specifically target Plasmodium as an effective antimalarial treatment, providing adequate selectivity can be obtained. Potential plasmepsin IX/X inhibitors should be assayed for inhibitory activity against the main human aspartic proteases and particularly CatD/E. An investigative rodent study conducted early in drug discovery would serve as an initial risk assessment of the potential hazards identified.

Barber J, Sikakana P, Sadler C, Baud D, Valentin JP, Roberts R. Toxicol Res (Camb). 2021 Feb 15;10(2):203-213LinkRestricted Access
Species-Specific Urothelial Toxicity With an Anti-HIV Noncatalytic Site Integrase Inhibitor (NCINI) Is Related to Unusual pH-Dependent Physicochemical Changes

GS-9695 and GS-9822 are next-generation noncatalytic site integrase inhibitors (NCINIs) with significantly improved potency against human immunodeficiency virus compared with previous drugs such as BI-224436.  These data provide useful insights to guide discovery and development of NCINIs, related compounds, and zwitterions.

Ruth A Roberts, Richard A Campbell, Phumzile Sikakana, Claire Sadler, Mark Osier, Yili Xu, Joy Y Feng, Michael Mitchell, Roman Sakowicz, Anne Chester, Eric Paoli, Jianhong Wang, and Leigh Ann Burns-Naas (2021)LinkOpenN/A
AI-based Language Models Powering Drug Discovery and Development. Submitted.

The discovery and development of new medicines is expensive, time-consuming, and often inefficient, with many failures along the way. Powered by artificial intelligence (AI), language models (LMs) have changed the landscape of natural language processing (NLP), offering possibilities to transform treatment development more effectively. Here, we summarize advances in AI-powered LMs and their potential to aid drug discovery and development.

Liu, Z, Roberts, R, Lal-Nag, M, Chen, X, Huang, R and Tong, W (2020) LinkRestricted AccessN/A
Justification for species selection for pharmaceutical toxicity studies. Toxicology Research

Toxicity studies using mammalian species are generally required to provide safety data to support clinical development and licencing registration for potential new pharmaceuticals…

Helen Prior, Richard Haworth, Briony Labram, Ruth Roberts, Alison Wolfreys and Fiona Sewell (2020)LinkOpenN/A
Can we panelise seizure? Toxicological Sciences, Online ahead of publication

Seizure liability remains a significant cause of attrition in drug discovery and development, leading to loss of competitiveness, delays, and increased costs. Current detection methods rely on observations made in in vivo studies intended to support clinical trials, such as tremors or other abnormal movements. These signs could be missed or misinterpreted; thus, definitive confirmation of drug-induced seizure requires a follow-up electroencephalogram study…

Roberts, RA, Authier, S, Mellon, D, Morton, M, Suzuki, I, Tjalkens, RB, Valentin, J-P and Pierson, J (2020) LinkOpenN/A
Deep Learning-Powered Drug-Induced Liver Injury Prediction Using Model-Level Representation. Submitted. Chemical Research in Toxicology

Drug-induced liver injury (DILI) is the most frequently reported single cause of safety-related withdrawal of marketed drugs. It is essential to identify drugs with DILI potential at the early stages of drug development. In this study, we describe a deep learning-powered DILI (DeepDILI) prediction model created by combining model-level representation generated by conventional machine learning (ML) algorithms with a deep learning framework based on Mold2 descriptors…

Li, T, Tong, W, Roberts, R, Liu, Z and Thakkar, S (2020) DeepDILI LinkRestricted AccessN/A
Advancing Genomics for Rare Disease Diagnosis and Therapy Development. Frontiers in Pharmacology 11, 1523.

Rare diseases affect only a small percentage of the population and are often chronic and potentially life-threatening. There are more than 7,000 known rare diseases, and yet fewer than 700 approved treatment options are available. Progress made with the use of emerging technologies such as next-generation sequencing (NGS) and bioengineering holds great promise in advancing rare disease diagnosis and therapy development (Liu et al., 2019)…

Liu, Z, Roberts, R, Shi, T, Mikailov, M and Tong, W (2020) LinkOpen
A decade of trends in toxicology. Tox Res, 9, 676-682

Here we look at popular trends and concepts in toxicology over the decade 2009–2019. The top 10 concepts included methodological approaches such as zebrafish and genomics as well as broader concepts such as personalized medicine and adverse outcome pathways. The total number and rank order for each of the top 10 were tracked year by year via PubMed with >9500 papers contributing to the analysis…

Sikakana, P and Roberts, R (2020) LinkRestricted AccessN/A
Opportunities for use of one species for longer-term toxicology testing during drug development: A cross-industry evaluation. Reg Tox Pharm. 113, 104624.

An international expert working group representing 37 organisations (pharmaceutical/biotechnology companies, contract research organisations, academic institutions and regulatory bodies) collaborated in a data sharing exercise to evaluate the utility of two species within regulatory general toxicology studies…

Prior et al (2020) LinkOpenN/A
Drug Repositioning for Noonan and LEOPARD Syndromes by Integrating Transcriptomics With a Structure-Based Approach. Frontiers in Pharmacology, 11, 927.

Noonan and LEOPARD syndromes (NS and LS) belong to a group of related disorders called RASopathies characterized by abnormalities of multiple organs and systems including hypertrophic cardiomyopathy and dysmorphic facial features. There are no approved drugs for these two rare diseases, but it is known that a missense mutation in PTPN11 genes is associated with approximately 50% and 70% of NS and LS cases, respectively…

Zhu, L, Roberts, R, Huang, R, Zhao, J, Xia, M, Delavan, B, Mikailov, M, Tong, W, and Liu, Z. (2020) LinkOpenN/A
Deep Learning on High-Throughput Transcriptomics to Predict Drug-Induced Liver Injury. Frontiers in Bioengineering and Biotechnology, 8. Online ahead of publication.

Drug-induced liver injury (DILI) is one of the most cited reasons for the high drug attrition rate and drug withdrawal from the market. The accumulated large amount of high throughput transcriptomic profiles and advances in deep learning provide an unprecedented opportunity to improve the suboptimal performance of DILI prediction. In this study, we developed an eight-layer Deep Neural Network (DNN) model for DILI prediction using transcriptomic profiles of human cell lines (LINCS L1000 dataset) with the current largest binary DILI annotation data [i.e., DILI severity and toxicity (DILIst)]. The developed models were evaluated by Monte Carlo cross-validation (MCCV), permutation test, and an independent validation (IV) set…

Li, T, Tong, W, Roberts, RA, Liu, Z, Thakkar, S (2020) LinkOpenN/A
Innovative models for in vitro detection of seizure. Toxicology Research 8 (6), 784-788.

Data show that toxicity to the central nervous system (CNS) is the most frequent cause of safety failures during the clinical phase of drug development. CNS endpoints such as seizure pose a safety risk to patients and volunteers and can lead to a loss of competitiveness, delays, and increased costs. Current methods rely on detection in the nonclinical rodent and non-rodent studies required to support clinical trials. There are two main issues with this approach; seizure may be missed in the animal studies and, even if seizure is detected, significant resource has already been invested in the project by this stage…

Rockley, K, Morton M and Roberts, R (2019) LinkRestricted AccessN/A
Can Transcriptomic Profiles from Cancer Cell Lines be Used for Toxicity Assessment? Toxicological Sciences, Chemical Research in Toxicology. 23 343-367.

In vitro toxicogenomics (TGx) has the potential to replace or supplement animal studies. However, TGx studies often suffer from a limited sample size and cell types. Meanwhile, transcriptomic data have been generated for tens of thousands of compounds using cancer cell lines mainly for drug efficacy screening. Here, we asked the question of whether these types of transcriptomic data can be used to support toxicity assessment…

Liu, Z, Zhu, L, Thakkar, S, Roberts, RA and Tong, W (2019) LinkOpenN/A
Towards Clinical Implementation of Next Generation Sequencing-based Genetic Testing in Rare Diseases: Where are we? Trends in Genetics. 45, 678-680.

Next-generation sequencing (NGS) technologies have changed the landscape of genetic testing in rare diseases. However, the rapid evolution of NGS technologies has outpaced its clinical adoption. Here, we re-evaluate the critical steps in the clinical application of NGS-based genetic testing from an informatics perspective. We suggest a ‘fit-for-purpose’ triage of current NGS technologies…

Liu, Z, Zhu, L, Roberts, RA and Tong, W (2019) LinkOpenN/A
Collaboration, Competition and Publication in Toxicology: view of British Toxicology Society members. Toxicology Research, 2019. E-pub ahead of print.

To ascertain attitudes to resourcing, collaboration and publication in toxicology, a survey was developed and distributed to British Toxicology Society (BTS) members. The survey comprised 14 questions with 5 response options (strongly agree; agree; conflicted; disagree; strongly disagree) and a free text box. One hundred completed surveys were received by the cut-off date for data analysis. Unsurprisingly, 60% of participants disagreed or strongly disagreed that toxicology research is adequately funded in the UK; only 12% agreed with this statement…

Walker, ES, Gill, JH and Roberts. RA (2019) LinkOpenN/A
Toxicogenomics: a 2020 vision. TiPS. 40: 92-103.

Toxicogenomics (TGx) has contributed significantly to toxicology and now hasgreat potential to support moves towards animal-free approaches in regulatorydecision making. Here, we discuss in vitro TGx systems and their potentialimpact on risk assessment. We raise awareness of the rapid advancement ofgenomics technologies, which generates novel genomics features essential forenhanced risk assessment. We specifically emphasize the importance of repro-ducibility in utilizing TGx in the regulatory setting…

Lui, Z, Huang, R, Roberts, R and Tong, W (2019). LinkOpenN/A
Drug Discovery and Development: biomarkers of neurotoxicity and neurodegeneration. Experimental Biology and Medicine. 243: 1037–1045

The discovery and development of new drugs are vital if we are to improve and expand treatment options available to improve outcomes for patients. Overall, therapeutic strategies fall into two broad categories: small molecules and biologics, although more recently there has been a growth in novel platforms such as miRNAs and oligonucleotides. On average, the development of a small molecule drug takes around 12 years and costs around $50m. Despite this huge investment of time and money, attrition remains a major challenge and very few molecules actually make it through to the market…

Walker, A, Imam, S and Roberts, RA (2018). LinkOpenN/A
Understanding drug targets: there’s no such thing as bad news. Drug Discovery Today, 23, 1925-1928.

How can small-to-medium pharma and biotech companies enhance the chances of running a successful drug project and maximise the return on a limited number of assets? Having a full appreciation of the safety risks associated with proposed drug targets is a crucial element in understanding the unwanted side-effects that might stop a project in its tracks. Having this information is necessary to complement knowledge about the probable efficacy of a future drug…

Roberts, RA (2018) LinkRestricted AccessN/A
Collaboration and competition: ethics in toxicology. Toxicology Research, 7, 576-585.

From animal research through adverse events in clinical trials to health scares around food contamination, toxicology has frequently been a focus of scientific and societal concern. As these concerns shift with each new drug, new technology or public health scare, how can toxicology stay current, relevant and ethical? Two of the biggest ethical challenges in pharmaceutical toxicology are the use of animals in testing and the high safety-related attrition rates in new drug development. Both of these require progress in the discipline that will only be driven by research funding. Yet, very little is invested in these two fields compared with investment in new efficacy models, new disease targets and new technologies…

Walker, ES and Roberts, RA (2018). LinkOpenN/A
Gene Signature Reveals Differences among Preclinical Testing Systems for Rat Liver. Front. Genet., 9, 1-10

Toxicogenomics (TGx) is an important tool to gain an enhanced understanding of toxicity at the molecular level. Previously, we developed a pair ranking (PRank) method to assess in vitro to in vivo extrapolation (IVIVE) using toxicogenomic datasets from the Open Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATEs) database. With this method, we investiagted three important questions that were not addressed in our previous study: (1) is a 1-day in vivo short-term assay able to replace the 28-day standard and expensive toxicological assay?…

Liu, Z, Delavan, B, Roberts, R and Tong, W (2018). LinkOpenN/A
Changes in the metabolome and microRNA levels in biological fluids might represent biomarkers of neurotoxicity: A trimethyltin study. Experimental Biology and Medicine, 243, 228-236

Neurotoxicity has been linked with exposure to a number of common drugs and chemicals, yet efficient, accurate, and minimally invasive methods to detect it are lacking. Fluid-based biomarkers such as those found in serum, plasma, urine, and cerebrospinal fluid have great potential due to the relative ease of sampling but at present, data on their expression and translation are lacking or inconsistent. In this pilot study using a trimethyl tin rat model of central nervous system toxicity, we have applied state-of-the-art assessment techniques to identify potential individual biomarkers and patterns of biomarkers in serum, plasma, urine or cerebral spinal fluid that may be indicative of nerve cell damage and degeneration…

Imam, S, He, Z, Cuevas, E, Rosas-Hernandez, H, Lantz, S, Sarkar, S, Raymick, J Robinson, B, Hanig, J, Herr ,D, MacMillan, D, Smith, A, Liachenko, S, Ferguson, S, O’Callaghan, J, Miller, D, Somps, C, Pardo, I, Slikker, W, Pierson, J, Roberts, R, Gong, B, Tong, W, Aschner, M, Kallman M-J, Calligaro, D and Paule M (2017) LinkRestricted AccessN/A
The Liver Toxicity Knowledge Base (LKTB) and Drug-Induced Liver Injury (DILI) Classification for Assessment of Human Liver Injury. Expert review of Gastroenterology and Hepatology. 12, 31-38.

Introduction: Drug-induced liver injury (DILI) is challenging for drug development, clinical practice and regulation. The Liver Toxicity Knowledge Base (LTKB) provides essential data for DILI study.

Areas covered: The LTKB provided various types of data that can be used to assess and predict DILI. Among much information available, several reference drug lists with annotated human DILI risk are of important…

Thakkar, S, Chen, M, Fang, H, Liu, Z, Roberts, R, Tong, W (2018). LinkRestricted AccessN/A
Computational Drug Repositioning for Rare Diseases in the era of Precision Medicine. Drug Discovery Today, 2, 382-394.

There are tremendous unmet needs in drug development for rare diseases. Computational drug repositioning is a promising approach and has been successfully applied to the development of treatments for diseases. However, how to utilize this knowledge and effectively conduct and implement computational drug repositioning approaches for rare disease therapies is still an open issue. Here, we focus on the means of utilizing accumulated genomic data for accelerating and facilitating drug repositioning for rare diseases…

Delavan, B, Roberts, R, Goldsmith, J, Fang, H, Thakkar, S, Huang, R, Bao, W, Tong, W and Liu, Z (2018). LinkRestricted AccessN/A
Lessons learned from two decades of anticancer drugs. TiPS 38, 852-872.

Tremendous efforts have been made to elucidate the basis of cancer biology with the aim of promoting anticancer drug development. Especially over the past 20 years, anticancer drug development has developed from conventional cytotoxic agents to target-based and immune-related therapies. Consequently, more than 200 anticancer drugs are available on the market. However, anticancer drug development still suffers high attrition during the later phases of clinical development and is considered to be a difficult and risky therapeutic category within the drug development arena…

Liu, Z, Delavan, B, Roberts, R and Tong, W (2017). LinkRestricted AccessN/A
In vitro to in vivo extrapolation (IVIVE) for drug-induced liver injury: A genome wide analysis using a drug pair ranking (DPRank) method. ALTEX.

Preclinical animal toxicity studies may not accurately predict human toxicity. In light of this, in vitro systems have been developed that have the potential to supplement or even replace animal use. We examined in vitro to in vivo extrapolation (IVIVE) of gene expression data obtained from The Open Japanese Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (Open TG-GATEs) for 131 compounds given to rats for 28 days, and to human or rat hepatocytes for 24 hours…

Liu, Z, Fang, H, Roberts, RA and Tong, W (2017). LinkRestricted AccessN/A
The Collaboration Gene. Royal Society of Chemistry blog

Collaborations play a vital role in innovation and in the pursuit of new translatable knowledge. These can range from very informal interactions through to the creation of start-up companies with unlimited opportunities for generation of societal and commercial value…

Roberts, RA (2016) LinkOpenN/A
Toxicology as an academic discipline in European Universities. Toxicology Letters, 254, 63.

No abstract available

Wallace, H, Roberts, R, Corsini, E, Bonefeld-Jorgensen, E, Orhan, H, Mach, M, Weiser, T, Carvalho, F, Iscan, M, Tsatsakis, A (2016) LinkRestricted AccessN/A
Target organ profiles in toxicity studies supporting human dosing: does severity progress with longer duration of exposure? Regulatory Tox. Pharm., 73, 737-746.

We have previously reported the profile of target organs (defined as organs showing histopathological changes) in rodent and non-rodent toxicity studies conducted prior to first-time-in-man (FTiM) for 77 AstraZeneca candidate drugs (CDs). Here, we test the assumption that toxicity is exacerbated by dosing duration by comparing the incidence and severity of target organ toxicities in these ≤ 6 week FTiM studies with those observed in subsequent subchronic/chronic (≥ 3 month) studies…

Roberts, RA, Callander, R, Knight, R and Boobis, A. (2015) LinkRestricted AccessN/A
Translational Biomarkers of Neurotoxicity: a HESI Perspective on the Way Forward. Tox Sci., 148, 332-340.

Neurotoxicity has been linked to a number of common drugs and chemicals, yet efficient and accurate methods to detect it are lacking. There is a need for more sensitive and specific biomarkers of neurotoxicity that can help diagnose and predict neurotoxicity that are relevant across animal models and translational from nonclinical to clinical data. Fluid-based biomarkers such as those found in serum, plasma, urine, and cerebrospinal fluid (CSF) have great potential due to the relative ease of sampling compared with tissues…

Roberts R.A, Aschner M., Calligaro D., Guilarte T.R., Hanig J. , Herr D.W, Hudzik, T.J., Jeromin, A., Kallman M.J. , Liachenko S., Lynch J.J. III, Miller D.B., Moser V.C. , O’Callaghan J.P. , Slikker W. Jr. , Paule, M.G. (2015). LinkRestricted AccessN/A
De novo LINE-1 Retrotransposition in HepG2 Cells Preferentially Targets Gene Poor Regions of Chromosome 13. Genomics. 104, 96-104.

Longinterspersednuclear elements(Line-1 orL1s) account for~17% of thehuman genome. While the majority ofhuman L1s are inactive, ~80–100 elements remain retrotransposition competent and mobilize through RNAintermediates to different locations within the genome. De novo insertions of L1s account for polymorphicvariation of the human genome and disruption of target loci at their new location…

Bojang, P., Anderton, M., Roberts R. and Ramos, K (2014) LinkRestricted AccessN/A
Target organ profiles in toxicity studies supporting human dosing: An assessment of recovery and chronic dosing. Reg Tox Pharm. 70 270-285.

We have previously reported the profile of target organs (defined as organs showing histopathological changes) in rodent and non-rodent toxicity studies conducted prior to first-time-in-man (FTiM) for 77 AstraZeneca candidate drugs (CDs). Here, we test the assumption that toxicity is exacerbated by dosing duration by comparing the incidence and severity of target organ toxicities in these ≤ 6-week FTiM studies with those observed in subsequent subchronic/chronic (≥ 3 month) studies…

Horner, S, Robinson, S, Callander, R, Lees, D and Roberts R (2014) LinkRestricted AccessN/A
An integrated characterisation of the functional, structural, pathological and serological events associated with the development of chronic doxorubicin-induced cardiotoxicity in rat. Toxicological Sciences, 140, 3-15.

Many efficacious cancer treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study, we have utilized a rat model of progressive doxorubicin (DOX)-induced cardiomyopathy, applying multiple approaches, including cardiac magnetic resonance imaging (MRI), to provide the most comprehensive characterization to date of the timecourse of serological, pathological, and functional events underlying this toxicity…

Cove-Smith, L, Woodhouse, N, Hargreaves, A, Kirk, J, Smith, S, Price, S, Galvin, M, Betts, C, Brocklehurst, S, Backenγ, A, Radford, J, Linton, K, Roberts, R, Schmitt, M, Dive, C, Tugwood, J, Hockings, P and Mellor, H (2013). LinkRestricted AccessN/A
Reducing Attrition in Drug Development: smart loading pre-clinical safety assessment. Drug Discovery Today. 19 341 – 347.

Entry into the crucial preclinical good laboratory practice (GLP) stage of toxicology testing triggers significant R&D investment yet >20% of AstraZeneca’s potential new medicines have been stopped for safety reasons in this GLP phase alone. How could we avoid at least some of these costly failures? An analysis of historical toxicities that caused stopping (‘stopping toxicities’) showed that >50% were attributable to target organ toxicities emerging within 2 weeks of repeat dosing or to acute cardiovascular risks. By frontloading 2-week repeat-dose toxicity studies and a comprehensive assessment of cardiovascular safety, we anticipate a potential 50% reduction in attrition in the GLP phase…

Roberts, RA, Kavanagh, S, Mellor, H, Pollard, C, Robinson, S and Platz, SJ (2014) LinkRestricted AccessN/A
Target organ toxicities in studies conducted to support first time in man dosing: an analysis across species and therapy areas. (2013) Regulatory Toxicology and Pharmacology 65 334 -343

An analysis of target organ toxicities in first time in man (FTiM) toxicity studies for 77 AstraZeneca candidate drugs (CDs) was conducted across a range of therapy areas. In the rodent, the most frequently affected organ was the liver followed by adrenal glands, kidney, spleen, bone marrow and thymus. In non-rodent, liver and thymus were the most frequently affected organs, followed closely by the testis and GI tract. The profile of affected organs was largely similar across the therapy areas of respiratory and inflammation, cardiovascular/gastrointestinal and CNS/pain. The oncology/infection therapy area differed with a larger range of organs affected…

Horner, Ryan, Robinson, Callander, Stamp and Roberts (2013). LinkRestricted AccessN/A
Epigenetics – Relevance to Drug Safety Science. Toxicology Research 1 3-6.

Epigenetics describes the study of heritable changes in gene expression that occur in the absence of a change to the DNA sequence. Specific patterns of epigenetic signatures can be stably transmitted through mitosis and cell division and form the molecular basis for developmental stage- and cell type-specific gene expression. Associations have been observed that endogenous and exogenous stimuli can change the epigenetic control of both somatic and stem cell differentiation and thus influence phenotypic behaviours and/or disease progression…

Priestley, C, Mellor, H, Duffy, P, Powell, H, Anderton M and Roberts, RA (2012) LinkRestricted AccessN/A
Toxicological and pathophysiological roles of reactive oxygen and nitrogen species, Toxicology 276: 85-94.

‘Oxidative and Nitrative Stress in Toxicology and Disease’ was the subject of a symposium held at the EUROTOX meeting in Dresden 15th September 2009. Reactive oxygen (ROS) and reactive nitrogen species (RNS) produced during tissue pathogenesis and in response to viral or chemical toxicants, induce a complex series of downstream adaptive and reparative events driven by the associated oxidative and nitrative stress. As highlighted by all the speakers, ROS and RNS can promote diverse biological responses associated with a spectrum of disorders including neurodegenerative/neuropsychiatric and cardiovascular diseases…

Roberts, RA, Smith, RA, Safe, S, Szaba, C, Tjalkens, RB and Robertson, F (2010) LinkRestricted AccessN/A