Thirteenth Annual Fragment-based Drug Discovery Meeting

CHI’s Drug Discovery Chemistry (DDC) meeting was held last week in San Diego. The event continues to grow, and this year hosted some 800 attendees, three quarters from the US and two thirds from biotech or pharma. The first DDC meeting in 2006 had just four tracks, of which FBDD is the only one that remains. The current event had nine tracks and three one-day symposia. There was always something interesting happening, and usually several – at one point three talks involving fragments were going simultaneously. Like last year, I’ll just try to give a few impressions.

What struck me most was the number of success stories, several involving clinical compounds. Last year we highlighted Pfizer’s discovery of a chemical probe against ketohexokinase (KHK); Kim Huard described how this was optimized to PF-06835919, the first and only KHK inhibitor to enter the clinic, which is now in phase 2 trials for NAFLD.

Another phase 2 compound was described by Paul Sprengeler (eFFECTOR Therapeutics). A handful of fragments designed from published work were characterized crystallographically bound to the kinase MNK1, and careful structure-based design resulted in eFT508, an MNK1/2 inhibitor which is being tested against various cancers.

A few years back we highlighted Genentech’s work on the kinase ERK2. In a lovely example of fragment-assisted drug discovery, Huifen Chen told “the convoluted journey of an ERK2 fragment series (with an HTS detour)”. SAR from the fragment series was used to inform the optimization of an HTS series originating from partner Array BioPharma, and was particularly useful for fixing some pharmacokinetic liabilities. Huifen emphasized the importance of using information from multiple strategies, ultimately leading to GDC-0994, which entered phase 1 trials for cancer.

Rounding up the list of clinical compounds, I heard through the grapevine that AbbVie’s dasabuvir, approved for hepatitis C, had fragments in its ancestry. I’d be interested to know more; though since success usually has many fathers, precise parentage can be tricky to ascertain.

Earlier stage success stories included the discovery of BI-9321, a highly selective inhibitor of NSD3-PWWP-1, which binds to methylated lysine residues in proteins. Jark Böttcher described how a collaboration between Boehringer Ingelheim and the Structural Genomics Consortium started with NMR and DSF-based screens of 1899 fragments to identify the cell-active chemical probe.

Jenny Viklund (Sprint Bioscience) described the discovery of potent, selective inhibitors of MTH1, a potential anti-cancer target. The project was successful, but unfortunately the molecules did not have the desired effect in cancer cell lines; this and other evidence helped to devalidate the target. Although undoubtedly disappointing, knowing what not to pursue is still important, and who knows – perhaps the target will turn out to be important in the future.

Finally, Steve Fesik (Vanderbilt) described a number of success stories against the KRAS protein, one of the holy grails of oncology. He also described how a fragment screen against a similarly hot target, the transcription factor MYC, failed utterly – the numerous compounds reported in the literature turned out to be artifacts or DNA intercalators. However, colleague Bill Tansey found that MYC interacts with the protein WDR5, and this protein-protein interaction turned out to be tractable, ultimately yielding potent inhibitors. This is a useful reminder that even if your target is not directly ligandable, biology is complicated enough that you may be able to modulate it through one of its partners.

Success sometimes requires breaking rules, as illustrated by the rule-of-5-defying drug venetoclax. Indeed, as noted by AbbVie’s Phil Cox, 18 of the 76 oral drugs approved since 2014 are bRo5s (beyond rule of 5). But if you’re going to break rules you should expect a harder path, and Phil described factors that correlate with success. Pete Kenny will be delighted to know that this has resulted in a new metric, AB-MPS, which is defined as the sum of the number of rotatable bonds, aromatic rings, and the difference of the ClogD from 3; values less than 12 are correlated with a higher probability of being orally bioavailable among AbbVie’s bRo5s.

Former guest blogger Brian Stockman described NMR-based functional screens he is doing with undergraduates at Adelphi University. Library acquisition can be challenging for a small organization, but happily Dean Brown at AstraZeneca has established an Open Innovation program for neglected diseases – if you’re interested and eligible you can receive a high-quality 1963-fragment library plated and ready for screening.

Of course there was plenty to learn about fragment-finding methods too, both in talks and in a discussion session led by Rod Hubbard (University of York and Vernalis). Microscale thermophoresis (MST) continues to be controversial, with researchers from a couple companies commenting that it’s fantastic the 20% of the time it works, while another company had success rates of ~95%. Thermal shift assays were also contentious, though Fredrik Edfeldt’s (AstraZeneca) method of adding urea or D₂O (see here) to improve the sensitivity created significant buzz.

Cryo-electron microscopy continues to make rapid strides for structurally characterizing difficult targets, such as membrane proteins. Christopher Arthur (Genentech) did not downplay the many technical hurdles, particularly in sample preparation, but he thought that 2 Å resolution structures would be routine within the next decade. Although they have yet to analyze fragment binding, this is only a matter of time.

Ben Cravatt (Scripps) discussed ligand discovery on a proteome-wide scale using electrophilic fragments. His group has currently discovered more than 2000 ligandable cysteine residues in human cells – an exciting if daunting number of potential new targets.

And in the category of now for something completely different, Josh Wand (University of Pennsylvania) described nanoscale encapsulation – in which individual proteins are confined in reverse micelles suspended in liquid pentane; the low viscosity increases tumbling time and thus resolution for NMR, while the miniscule volume increases the concentration of protein and any accompanying fragments. This allows detection of extraordinarily weak interactions (dissociation constants of several hundred millimolar or worse). The technique is limited to very polar fragments because less polar ones would diffuse into pentane, but it would be interesting to see if a fluorocarbon replacement for the hydrocarbon allowed a wider range of fragments to be tested.

I could keep writing but I’ll stop here, hopefully before you stop reading; please leave comments. There are still several good events coming up this year, and mark your calendar for next year, when DDC returns to San Diego April 8-12, 2019!