With the rapid expansion in the development and clinical utility of immune checkpoint inhibitors (ICIs) for oncology, the continual evaluation of the safety profile of such agents is imperative. The safety profile of ICIs as monotherapy is dominated by immune-related adverse events, which can be considered as an extension of the mechanism of action of these immunomodulatory drugs. Further to this, an emerging theme is that ICI treatment can significantly impact upon the tolerability of co-administered medications. Numerous reports in literature indicate that ICIs may alter the immunological perception of co-administered drugs, resulting in undesirable reactions to a variety of concomitant medications. These reactions can be severe in manifestation, including hepatotoxicity and Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), but may also have detrimental impact on malignancy control. To minimize the impact of such drug−drug interactions on patients, it is imperative to identify medications that may cause these reactions, understand the underlying mechanisms, consider the timing and dosing of comedication, and explore alternative medications with comparable efficacies. Improving our understanding of how concomitant medications affect the safety and efficacy of ICIs can allow for potential culprit drugs to be identified/removed/desensitized. This approach will allow the continuation of ICI therapy that may have been discontinued otherwise, thereby improving malignant control and patient and drug development outcomes.

Author: Grice, Sophie; Olsson-Brown, Anna; Naisbitt, Dean J; Hammond Sean; Chem. Res. Toxicol; 37, 1086-1103

View Here

Drug-induced renal injury (DIRI) causes >1.5 million adverse events annually in the USA alone. Although standard biomarkers exist for DIRI, they lack the sensitivity or specificity to detect nephrotoxicity before the significant loss of renal function. In this study, we describe the creation of DIRIL – a list of drugs associated with DIRI and nephrotoxicity – from two literature datasets with DIRI annotation, confirmed using FDA drug labeling. DIRIL comprises 317 orally administered drugs covering all 14 anatomical, therapeutic and chemical (ATC) classification categories. Of the 317 drugs, 171 were DIRI-positive and 146 were DIRI-negative. DIRIL will be a relevant and invaluable resource for discovery of new approach methods (NAMs) to predict the occurrence and possible severity of DIRI earlier in drug development.

Author:Skylar Connor, Ting Li, Yanyan Qu, Ruth A Roberts, Weida Tong, Generation of a drug-induced renal injury list to facilitate the development of new approach methodologies for nephrotoxicity, Drug Discovery Today, Volume 29, Issue 4, 2024, 103938

View Here

There are many different approaches to drug discovery in academia, some of which are based broadly on the industrial model of discovering novel targets and then conducting screening within academic drug discovery centres to identify hit molecules. Here we describe our approach to drug discovery, which makes more efficient use of the capabilities and resources of the different stakeholders. Specifically, we have created a large portfolio of drug projects and conducted small amounts of derisking work to ensure projects are investment ready. In this feature we will describe this model, including its limitations and advantages, since we believe the ideas and concepts will be of interest to other academic institutions and consortia.

Author: Murray AJ, Cox LR, Adcock HV, Roberts RA. Academic drug discovery: Challenges and opportunities. Drug Discov Today. 2024 Apr;29(4):103918.

View Here

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.

Author: 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.

View Here

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.

Author: Coltman NJ, Roberts RA, Sidaway JE. Data science in drug discovery safety: Challenges and opportunities. Experimental Biology and Medicine. 2023;248(21):1993-2000

View Here

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.

Author: Gardner J, Hammond S, Jensen R, et al. Glycolysis: An early marker for vancomycin-specific T-cell activation. Clin Exp Allergy. 2024; 54: 21-33

View Here

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.

Author: 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):126-140

View Here

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.

Author: 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, 105486

View Here

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.

Author: 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 138-145

View Here

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.

Author: 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)

View Here

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.

Author: 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.

View Here

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.

Author: 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, 2023

View Here

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.

Author: 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.

View Here

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.

Author: Sean Hammond, Xiaoli Meng, Merrie Mosedale, Dean J. Naisbitt, Toxicology Letters, Volume 373, 2023, Pages 148-151

View Here

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).

Author: Thomson P, Hammond S, Naisbitt DJ. . Clin Exp Allergy. 2022 Dec; 52(12):1379-1390

View Here

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.

Author: Ruth Roberts, Kim Rockley, Emma Marczylo, Heather Wallace, Toxicology Research, Volume 11, Issue 5, October 2022, Pages 709–710,

View Here

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.

Author: Hammond S, Olsson-Brown A, Grice S, Naisbitt DJ. Clin Exp Allergy. 2022 May;52(5):600-603.

View Here

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.

Author: Xi Chen, Ruth Roberts, Weida Tong, Zhichao Liu, Toxicological Sciences, Volume 186, Issue 2, April 2022, Pages 242–259

View Here

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).

Author: 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,

View Here

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.

Author: Demarta-Gatsi, C., Donini, C., Duffy, J., Sadler, C., Stewart, J., Barber, J. A., & Tornesi, B. (2022) Birth Defects Research, 114(10), 487–498.

View Here

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.

Author: Hammond S, Olsson-Brown A, Gardner J, et al; Journal for ImmunoTherapy of Cancer 2021;9

View Here

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. Author: Barber J, Sikakana P, Sadler C, Baud D, Valentin JP, Roberts R. Toxicol Res (Camb). 2021 Feb 15;10(2):203-213 View Here

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. Author: 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) View Here

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.

Author: Liu, Z, Roberts, R, Lal-Nag, M, Chen, X, Huang, R and Tong, W (2020)

View Here

Toxicity studies using mammalian species are generally required to provide safety data to support clinical development and licencing registration for potential new pharmaceuticals… Author: Helen Prior, Richard Haworth, Briony Labram, Ruth Roberts, Alison Wolfreys and Fiona Sewell (2020) View Here

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…

Author: Roberts, RA, Authier, S, Mellon, D, Morton, M, Suzuki, I, Tjalkens, RB, Valentin, J-P and Pierson, J (2020)

View Here

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…

Author: Li, T, Tong, W, Roberts, R, Liu, Z and Thakkar, S (2020) DeepDILI

View Here

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…

Author: Prior et al (2020)

View Here

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…

Author: Li, T, Tong, W, Roberts, RA, Liu, Z, Thakkar, S (2020)

View Here

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…

Author: Zhu, L, Roberts, R, Huang, R, Zhao, J, Xia, M, Delavan, B, Mikailov, M, Tong, W, and Liu, Z. (2020)

View Here

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…

Author: Rockley, K, Morton M and Roberts, R (2019)

View Here

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…

Author: Liu, Z, Zhu, L, Thakkar, S, Roberts, RA and Tong, W (2019)

View Here

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…

Author: Liu, Z, Zhu, L, Roberts, RA and Tong, W (2019)

View Here

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…

Author: Walker, ES, Gill, JH and Roberts. RA (2019)

View Here

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…

Author: Walker, A, Imam, S and Roberts, RA (2018).

View Here

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…

Author: Roberts, RA (2018)

View Here

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…

Author: 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)

View Here

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…

Author: Thakkar, S, Chen, M, Fang, H, Liu, Z, Roberts, R, Tong, W (2018).

View Here

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…

Author: Delavan, B, Roberts, R, Goldsmith, J, Fang, H, Thakkar, S, Huang, R, Bao, W, Tong, W and Liu, Z (2018).

View Here

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…

Author: Liu, Z, Delavan, B, Roberts, R and Tong, W (2017).

View Here

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…

Author: Liu, Z, Fang, H, Roberts, RA and Tong, W (2017).

View Here

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…

Author: 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).

View Here

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…

Author: 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).

View Here

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…

Author: Roberts, RA, Kavanagh, S, Mellor, H, Pollard, C, Robinson, S and Platz, SJ (2014)

View Here