This week thousands of chemists converged on the venerable city of Boston for the Fall National ACS meeting. One brief but rich symposium was entitled “Best practices in fragment-based drug design,” organized by Amy Hart, David Marcoux, and Heidi Perez (BMS).
After an introductory presentation by me, Anil Padyana described FBDD at Agios. The company is focused on metabolic enzymes, many of which have dynamic, shallow, and polar active sites – challenging even for fragments! Indeed, a summary of 11 targets screened using a variety of methods revealed generally low hit rates, usually < 3%. The company’s first approved drug came out of an HTS screen against IDH2 of 80,000 compounds that yielded just 24 hits. The molecule that ultimately led to enasidenib was essentially a (large) fragment, with 21 atoms. Agios’ current fragment library is
just over 5000 about 10,000 molecules, though they are in
the process of expanding this to 20,000 – perhaps part of a general trend.
Given the history of enasidenib, they are including molecules beyond the rule of 3, with an upper molecular weight limit of 350 Da, far higher than most respondents in our recent poll.
Cullen Cavallaro presented an early, though still unpublished, FBDD story from BMS: KAT II, a brain enzyme implicated in schizophrenia. Screening 3700 fragments using NMR, SPR, and TSA yielded 236 hits, only 6 of which were common to all methods. All 236 hits were soaked into crystals of KAT II, resulting in 43 structures, 13 of which bound in the active site. Strikingly, 12 of these contained carboxylic acids, which generally don’t cross the blood brain barrier. The lucky thirteenth fragment showed no activity in an enzymatic assay, no thermal stabilization, and only a marginal STD NMR signal. However, through a combination of library synthesis and structure-based design the researchers were able to obtain nanomolar inhibitors. Unfortunately the project was stopped when BMS exited neuroscience.
Anna Vulpetti provided an overview of work done by her and her Novartis colleagues to discover inhibitors of Factor D. A high-throughput screen of the serine protease didn’t yield anything useful, but a combination of fragment screening and structure-based design led to multiple series of inhibitors. Anna is a proponent of fluorine NMR, and Novartis has recently expanded its fluorinated fragment library to 4000 members. Like Agios, they have chosen to include some larger fragments, up to 350 Da.
Finally, David Norton described the initial work done at Astex to discover an orally available ERK1/2 inhibitor, which entered phase 1/2 clinical trials in May of this year. We highlighted some of this work a couple months ago so I won’t cover it in detail, but among other lessons David emphasized the importance of initial fragment optimization before starting to grow.
There were plenty of fragment talks outside the symposium too. Last year we highlighted Ben Cravatt’s strategy for performing fragment screening in cells. Chris Parker, the first author on that paper, has just launched his independent academic career at Scripps Florida, and provided an update. Chris noted that, for phenotypic screening, the approach is essentially a target-finding method, and indeed more than 4000 proteins have been identified, varying over five orders of magnitude in abundance. Having proper controls is critical, and recent efforts include screening pairs of enantiomeric fragments and looking for differences.
Taekyu Lee provided an update of the Vanderbilt MCL-1 program, most recently described in this paper. Some of the molecules shown have low picomolar affinity, mid nanomolar cell activity, and are more than 10,000-fold selective for MCL-1 over BCL-2 and BCL-xL. The program was partnered with Boehringer Ingelheim earlier this year, and they’ve got competition: four other molecules have entered the clinic.
Covalent fragments were also a theme. Peter Wipf (University of Pittsburgh) described the construction of a 300 compound “mercaptophilic” library. In contrast to other academic reactive fragment libraries we’ve covered (see here, here, and here), this one contains a wide variety of different warheads with varying reactivities.
Finally, Jeff Neitz (UCSF) described efforts against Taspase-1, which is involved in cancer cell proliferation. A high-throughput screen of 242,000 molecules yielded seven chemical series – all of which ultimately proved to be artifacts. The enzyme is a threonine protease but contains a cysteine residue near the active site, so the researchers conducted a Tethering screen with 1280 disulfide-containing molecules, which led to 64 hits in five classes. Converting the disulfide to more drug-like warheads ultimately led to nanomolar molecules with cell-based activity, and the researchers even had some success removing the warhead entirely.
If you missed the meeting, you still have time to catch what should be an epic conference: FBLD 2018 returns to San Diego where it originated ten years ago. People still talk fondly about that meeting, so don’t miss this one!