Fifth Annual Fragment-Based Drug Discovery

The first of two conferences in 2010 exclusively devoted to fragment-based drug discovery concluded in San Diego this week, and I thought I’d jot down some observations while my memories are still fresh.

The pre-conference short courses were quite successful (and I’m hopefully only slightly biased by the fact that Teddy and I were both instructors). Participants included folks with considerable experience in fragments, which allowed good discussion.

One talk from the conference that stands out in my mind was by Sandy Farmer of Boehringer Ingelheim. BI is a relative late-comer to fragment-based methods, really only starting in late 2004. Sandy described how fragment efforts are run in parallel with HTS. They use an intentionally modest fragment library of 2000 diverse compounds; increasing the size of this library tended to overwhelm downstream efforts. Fragments are confirmed using multiple assays, including SPR and size-exclusion chromatography coupled with mass spectrometry, with crystallography playing a pivotal role in determining which fragments to advance. Part of the challenge at BI has been getting chemists to accept FBS, or “faith-based synthesis,” particularly where initial fragments have low affinities. A focus on ligand efficiency helps, as do organizational strategies such as establishing a dedicated group of chemists focused on fragment projects.

Often at conferences you hear about success stories, but sometimes the continuing challenges are more instructive, as when Ravi Kurumbail at Pfizer discussed his efforts to discover drug-like inhibitors of the serine protease Factor XIa. One of the sobering findings was that, although a functional assay of 2500 fragments yielded a 6.5% hit rate, adding 0.01% detergent eliminated activity and revealed most ‘hits’ as false positives. Even one crystallographically characterized fragment with an apparent IC50 of 75 micromolar turned out to be an artifact after subsequent analysis – a reminder to always be vigilant at higher concentrations.

But back to success stories: Daniel Wyss gave an update on the BACE program from Merck (legacy Schering-Plough, which has run more than 30 fragment screens on various targets). We highlighted a couple publications resulting from this effort earlier this year. It turns out there are now three molecules from this program in early clinical trials – a clear indication of the importance of this target and the utility of fragment screening.

Finally, Rick Artis, formerly of Plexxikon (now Elan) gave an update on the PLX4032 Raf kinase program. This project demonstrates the potential for fragment-based efforts to move quickly: it was started in February 2005, the clinical candidate was identified in January 2006, the IND was filed in September, and the first patient was dosed in November of that year. The molecule has continued to move at warp speed through the clinic: it is now partnered with Roche in Phase III testing for metastatic melanoma, and was recently profiled in the New York Times. This lengthy but excellent article is well worth reading for a bit of perspective when life in the lab gets you down.

These are just a few of many nice talks and breakout discussions. I know that at least some readers of this blog were there – what were your impressions?