Drug Discovery


Table 1: The top 10 selling prescription drugs in the United States in 2011. Seven drugs have their origins from natural product sources


interviewing 52 individual HTS lab directors3. A year later, Fox and colleagues surprised the drug discovery world by reporting that up to 63 drug candidates, obtained from HTS efforts from the earlier 1990s to 2000, were indeed in Human clin- ical trials4. Does it mean that we can declare suc- cess of CC and HTS in providing us with the much needed drugs? Clearly, it is a sharp contrast between the Lahana editorial with no leads in sight and the Fox reports with up to 63 candidates in Human clinical trials. Almost 11 years later, one would expect to see at least a favourable outcome of some of these candidates and then we can col- lectively declare success. With limited information at hand, it is an impossible task to track each of the anonymous 63 clinical candidates through their trials and approval processes.


Scannell and colleagues, in a recent review, reported for the first time a thoughtful analysis of R&D efficiency over a 60-year period5 and may provide us with a partial answer as to the success or failure of CC and HTS. They report that with an 800-fold increase in CC output during the 1980s and 1990s resulting in large chemical libraries, innovations in HTS including a 10-fold cost reduc- tion in testing these libraries, and vast improve- ments to the R&D process including outsourcing, the number of new drug approvals has halved roughly every nine years since the 1950s and up to the 2010 approvals – an 80-fold fall in productivi- ty5. Their analysis seems to point towards failures rather than successes of CC and HTS. However, a more optimistic view was recently presented by Berggren and colleagues at McKinsey & Company, addressing the crisis in the R&D productivity with a five-year forecast in drug innovation6. The prob- ability of success (POS) is much higher in their forecast with an average annual number of approvals/launches to be above 30 during a five- year period (2011-15), and with a rapid decline to


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below 10 in 2016. Their positive outlook seems to be driven by the unique number of novel molecules in development and reaching 7,709 compounds in 2011. They further estimate the total number of novel compounds between 2006 and 2011 to be more than 13,000 potential drug products, based on their pipeline analysis of the Pharmaprojects pipeline database6. Berggren assessment is sugges- tive of a success if these 13,000 compounds were indeed the fruits of CC and HTS; but their outlook of potential disaster by 2016 somehow contradicts the success and questions whether the industry can indeed generate additional 13,000 novel com- pounds beyond 2015?


Chemical library: good or bad? Like many of my colleagues who are in the busi- ness of running chemical screening operations in Academia, we are often being told by our cus- tomers that the libraries we use in HTS are ‘no good’ since their friends were extremely lucky in finding hit(s) using someone else’s library; and sometimes even criticised by colleagues on grant review panels that the libraries to be used for screening are also ‘no good’. I often wondered whether this is an academic naivety problem to do with the novelty of chemical screening or there was an underlining message in there. When I joined Memorial Sloan-Kettering Cancer Center in 2003 to set up the HTS Lab, I was instructed by a par- ticular member of faculty to purchase the ChemBridge DIVERSet E library containing 50,000 compounds and as he put it “many people have screened it and published on it” as their selec- tion criteria for a chemical library; further adding “if no one has published on it then it will be hard to publish on it in the future”. I found their instructions and insistence remarkable considering the fact that they are chemists by training. Instead, I took the simplest approach to building what I


Drug Discovery World Spring 2013


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