Rushing to abandon tQT


Drug discovery always involves the continuous reassessment of the benefit-risk balance: from the first target identification all the way to the choice of patient population most suited to a new drug.
This paper (BioCentury (2013) Vol. 21,No.30 Page A1-A4) considers the call by the FDA and key Pharma stakeholders for the fine tuning of the benefit-risk evaluation during the cardiovascular safety de-risking of molecules: in particular with regards to QT signal prolongation, proarrhythmia and Torsades de Pointes (TdP) risk.
Following the withdrawal of eight drugs from the US market in the 1990s, a link between the inhibition of the hERG potassium channel, prolongation of the QT signal and elevated risk of TdP was made. Now, identification of pharmacological selectivity over inhibition of the hERG channel is standard in drug discovery programs. Further preclinical evaluation in animals and ultimately costly thorough QT trials (tQT) are employed to further clarify the risk / safety margins of development compounds.
It is now considered that information regarding QT prolongation, alone, is an insufficient predictor of TdP. Currently a 5-15 millisecond prolongation of the QT signal is considered a clinical risk, with >15 millisecond prolongation considered a serious clinical concern. The journal suggests that the focus of QT prolongation under the current FDA guidelines may have ‘killed’ development compounds that do not cause fatal arrhythmia.
The FDA, in consultation with pharma companies, clinicians and academics, want to abandon tQT studies by 2015, replacing them with a preclinical assay suite better able to detect proarrhythmia side effects than existing assays. The proposed suite would be:
• Functional Voltage clamp studies on several cardiac ion channels including hERG, Na1.5, CaV1.2, KvLQT1 and Kir2.1.
• Human stem cell derived ventricular cardiomyocytes, to look at the repolarization effects of a compound.
• Computational modelling of cardiomyocytes, based on input from the studies above, to predict early afterdepolarisation and action potential duration, both now considered predictors of the risk of a compound triggering arrhythmias.
The deadline is laudable, however achieving industry wide consensus by 2015 as to the assay suite’s format and interpretation of results may prove challenging. Replacing tQT would no doubt save money and resource for late stage preclinical and early clinical development. It will be important that the latest scientific understanding of repolarisation gives rise to clear guidelines to the discovery scientist. If research groups opt to prosecute molecules with a known hERG and QT prolongation liability, what ‘blend’ of pharmacology in the other ion channels is acceptable? Voltage clamp studies may still prove costly and resource consuming in an early drug discovery setting. For those hoping that the new assay suite and guidelines will significantly expedite and broaden drug discovery, choosing to sail close to the guidelines and navigating through them may take longer than anticipated.

Current salary trends in science


The article “What are you worth?” in the New Scientist 2014 Career Guide by Jessica Hamzelou, based on the September 2013 salary survey across the scientific sector (over 5000 participants), has revealed a rather gloomy picture. The main message from the collected data is that the scientists across the UK, Europe and North America have taken a pay cut since 2012. The UK has seen the worst drop in average salary – 8 percent down to £32,960. The scientists in North America have been affected the least: on average they are now earning $1440 less ($72470 in 2013). The economic recession of 2008 is the most obvious reason for such austerity with its effect still being felt across the countries five years on. The severe spending cuts by the Coalition Government in the UK, however, have had further undermining effect on the British science industries – in fact, the salaries in the UK haven’t yet recovered to their 2008 level. The lowest earners are those working in chemistry, particularly in academia, and the highest – in oil and gas industry.
The most worrying result of the 2013 survey is the still-present gap in the salaries of men and women, which grows with the employee’s experience. Women with more than 20 years of experience earn on average £9500 less than men in the UK, and $17,400 less – in North America. Discrimination is still one of the major causes behind the gender based salary differences, which was highlighted by Professor Jo Handelsman’s (Yale University) experiment, mentioned in the article. She sent fictional job applications from “John” and “Jennifer” to various research organisations. “John”, who had identical qualifications and job experience to “Jennifer”, was always rated as the most competent candidate than “Jennifer” and was offered a higher salary.
What do scientists lose their sleep over at the present? Their job prospects. Around half of the surveyed participants across all countries confessed that their current employment situation looked poor; with around a third of all respondents said they didn’t expect to work for their present employer longer than a year

Mimicking Life with Chemistry: An Historic Fascination Still As Current As Ever


The 8th December last year saw the unfortunate passing of Sir John ‘Kappa’ Cornforth, winner of the 1975 Nobel Prize in Chemistry, and emeritus professor here at the University of Sussex. Cornforth made his name in the field of chemistry by studying the mechanisms by which chemical reactions occur in the body. In particular, he studied the biosynthesis of cholesterol, with pioneering experiments using intermediates radiolabelled with carbon-14. Using this technique, he correctly identified each of the 14 biosynthetic steps at a regio- and stereochemically precise level. This work led to the awarding of the Nobel Prize in 1975, “for his work on the stereochemistry of enzyme-catalyzed reactions”. tom
1975 was also the year that Cornforth was awarded a professorship at the University of Sussex. This marked a subtle change in the direction of his research; he was given the ambitious task of designing a compound to act as an analogue for the enzyme hydratase. This practice of mimicking life with science is one that has engaged scientists for centuries, from wildly ambitious Victorian attempts to recreate life using electricity, to modern research directed by our ever-widening understanding of biochemistry. The use of biological mimetics within medicinal chemistry is a fairly obvious one. If analogues of biological molecules, such as DNA or polypeptide secondary structures, could be effectively used to target their respective protein binding sites, then we could utilise this to design competitive inhibitors of a wide range of therapeutic targets in the body. The ever growing body of publications demonstrate our continuing advancement in this area.
The Tavassoli group at the University of Southampton made recent headway in the field of DNA mimetics, with work identifying triazole groups as possible bioisosteres for phosphodiester linkers in a synthetic DNA backbone (Angew. Chem. Int. Ed. 2014, 53, 1 – 5). The group has been carrying out work on the hypothesis that the ‘click’ chemistry associated with triazoles could be integrated into DNA synthesis, providing a potential tool for joining two individual strands of DNA. The work discussed within the paper builds on previous work carried out by the group, and tests the biocompatibility of click linked DNA plasmids in human cells.
tom2
In order to test this, the Tavassoli group synthesized a plasmid containing a ‘click-linked’ mCherry fluorescent gene. The plasmid was then microinjected into a breast cancer cell line (MCF-7), and incubated for 24 hours. After the incubation period, approximately 90% of the cells exposed to the mCherry plasmid were found to display the red-fluorescent phenotype associated with mCherry expression, demonstrating that the triazole group is tolerated as an alternative to phosphodiester linkers by human DNA transcriptase enzymes.
The plasmid used only contains one ‘click’ linked triazole isostere, but it will be interesting to see to what extent the phosphodiester bridges can be substituted before the synthetic plasmid is no longer tolerated by the cell. Could techniques like this affect DNA synthesis in the laboratory in a similar fashion to the impact native chemical ligation first had on polypeptide synthesis?
A full obituary of Sir John Cornforth written by emeritus professor Jim Hanson and published in Nature can be found at http://dx.doi.org/10.1038/506035a.

Overview of trends in UK drug discovery


A recent paper in Nature Reviews Drug Discovery from Cathy Talau-Stewart & Caroline Low (formerly of the Imperial Drug Discovery Centre) and Nicola Marlin (Thomson Reuters) attempts to survey the current trends in the UK for academic drug discovery. Following on from a similar article by Stephen Frye in 2011, the data presented captures the therapeutic areas, business models, size/scope and staff experience level across the various UK institutions. Interestingly, most of the groups that responded to the survey (details contained in the supplementary information available on line) were from ‘traditional’ academic groups – implying that academics were directing their own research increasingly towards drug discovery funding sources – rather than bespoke drug discovery centres. This is reflected in the relatively low levels of industry experience within these academic groups, with only 40% of the lead directors having at least 5 years’ industrial experience.
In terms of capabilities, as expected, the majority of groups lacked the typical infrastructure found in ‘big pharma’ discovery teams – i.e. DMPK and HTS facilities – and reflecting the origin of most of the groups, the main driver for research was still papers and student training.
Interestingly, the therapeutic areas investigated are broadly the same as those in the US – with cancer & infectious disease dominating – presumably reflecting both target tractability and funding accessibility.
The most striking observation in the article is around funding, for which stark differences emerge between the UK and US environments. In the US, the government funds a significantly larger proportion of drug discovery, whilst EU and industry funding are still relatively minor components of UK funding.
The article takes an overall positive tone regarding the future opportunities presented, particularly if more coordinated efforts are made to support this emerging sector, however clear funding gaps exist coupled with an appropriate approach to the inherent risks of drug discovery and their incompatibility with some standard academic metrics.
blog