“The target safety evaluation was perfect. Our toxicologist was very happy with the final document as was the project team. Not only was the document great, it was delivered on time and the turn-around time for the edits was outstanding. I have no doubt that we will be using your services in the future.”
“I wanted to let you know that, after including your expert report into the IB, the Health Authority have approved both the IB as well as the clinical protocol amendment switching the contraception method from highly affective to effective, without any further questions or comments.
This is a very good news for the project, and clinical studies can continue as planned. Thank you very much for all your support, it was a great pleasure collaborating with you. I have greatly appreciated your thorough assessment as well as responsive and friendly manner, and your input made a key difference for the project progression.”
Preclinical Project Manager, Leading Global Pharmaceutical Company
A valued client, BugWorks Research, approached ApconiX to help them investigate the effect of intracellular pH on the inhibition of hERG potassium channel. At different pH, molecules might carry a different charge, depending on their structure. This may affect the molecule’s activity at hERG. Their enquiry followed some unexpected hERG inhibition by their compounds and the discovery of a paper published in 2016 by Wang et al. The paper showed that dofetilide, a known hERG blocker, had a quicker onset of effect at lower intracellular pH than under standard conditions. As shown in Figure 1.
Figure 1: Decreased time to effect of dofetilide at intracellular pH 6.2 versus pH 7.2 (from Wang et al., 2016)
Electrophysiology experiments were performed on the Patchliner automated patch-clamp system (Nanion Technologies). These experiments showed no significant difference in the onset of dofetilide inhibition at lower intracellular pH, as illustrated in figure 2.
Figure 2: No change in time to effect of dofetilide on hERG current at pH 6.3 versus pH 7.3.
There is limited literature in this area. ApconiX found a second paper by Du et al., 2011, which reported no effect of intracellular pH on hERG inhibition by dofetilide, contesting Wang’s original data.
Based on data from ApconiX and others, it is unlikely that intracellular pH is affecting the onset of hERG inhibition. Changes in intracellular pH that might affect the charge of a molecule does not, in this case, explain unexpected hERG inhibition.
Du et al (2011) Enhanced inhibitory effect of acidosis on hERG potassium channels that incorporate the hERG1b isoform. Biochem Biophys Res Comm 405, 222–7
Wang et al. (2016) Role of the pH in state-dependent blockade of hERG currents. Scientific Reports 6: 32536
“Your data turnaround time is incredibly good and it really helps us track the SAR and progress our compounds in a rapid and efficient manner. Thanks ApconiX for your wonderful support to Bugworks.”
V Balasubramanian, PhD, Bugworks Research India Pvt. Ltd.
“Working with ApconiX has been effortless! They have provided high quality target safety assessments with a focus on comprehensive interpretation of findings. The information provided has helped contribute to decisions on activities when moving early molecules forward. ApconiX constantly meets or exceeds timelines, while still providing flexibility to fit in last minute requests without impacting previously scheduled work. It has been a pleasure to work with Ruth and her team.”
“The support that we received from the ApconiX team has been excellent and they have helped us both in developing our nonclinical safety thinking and in providing direct support for the clinical trial application. We’re looking forward to continuing our collaboration as we progress our exciting new medicines into later-stage development and hopefully the clinic”
Dr. David Cook, Chief Scientific Officer, Blueberry Therapeutics
“ApconiX has provided hERG data to Redx Pharma from June 2016 to help support our discovery projects. Data turnaround times over this period have been rapid (under 1 week) and this has been critical in progressing projects quickly; outsourcing the assay with this turn-around has had no impact on our “design-make-test” cycle times.
Additionally, ApconiX’s approach is very collaborative providing expert advice on these data as part of their service. Another vital component to this screening is flexibility over compound numbers which enables us to maintain progress during the peaks and troughs of compound supply and prevents delays which can occur if you have to wait to reach a trigger point for submission of an assay.”
“We would not be here without your excellent input and help. You and ApconiX have been absolutely fantastic. Great planning and execution…..strong, straightforward communication…..pragmatic and a strong sense of team”