248th ACS National Meeting

The Fall ACS National Meeting was held in my beautiful city of San Francisco last week, and a number of topics of interest to Practical Fragments were on the agenda.

First up (literally – Sunday morning) was a session on pan-assay interference compounds (PAINS) organized by HTSPAINS-master Mike Walters of the University of Minnesota. Mike developed his interest in PAINS like many – from painful experience. After screening 225,000 compounds against the anti-fungal target Rtt109, he and his group found several hits that they identified as PAINS, but not before spending considerable time and effort, including filing a patent application and preparing a manuscript that had to be pulled. One compound turned out to be a “triple threat”: it is electrophilic, a redox cycler, and unstable in solution.

Mike had some nice phrases that were echoed throughout the following talks, including “subversively reactive compounds” and SIR for “structure-interference relationships,” the evil twin of SAR. To try to break the “PAINS cycle” Mike recommended more carefully checking the literature around screening hits and close analogs (>90% similarity). Of course, it’s better if you don’t include PAINS in your library in the first place.

Jonathan Baell (Monash), who coined the term PAINS back in 2010, estimated that 7-15% of commercial compounds are PAINS, and warned that even though PAINS may be the most potent hits, they are rarely progressable, advice that is particularly needed in academia. For example, the majority of patent applications around the rhodanine moiety come from academia, whereas the majority of patent applications around a more reasonable pharmacophore come from industry. Jonathan also warned about apparent SAR being driven by solubility. Finally, he noted that while it is true that ~6.5% of drugs could be classified as PAINS, these tend to have unusual mechanisms, such as DNA intercalation.

As we discussed last week, anyone thinking about progressing a PAIN needs to make decisions based on sound data. R. Kip Guy (St. Jude) discussed an effort against T. brucei, the causative agent of sleeping sickness. One hit from a cellular screen contained a parafluoronitrophenyl group that presumably reacts covalently with a target in the trypanosome and was initially deemed unprogressable. However, a student picked it up and managed to advance it to a low nanomolar lead that could protect mice against a lethal challenge. It was also well tolerated and orally bioavailable. Kip noted that in this case chemical intuition was too conservative; in the end, empirical evidence is essential. On that note he also urged people to publish their experiences with PAINS, both positive and negative.

There were a scattering of nice fragment talks and posters. Doctoral student Jonathan Macdonald (Institute of Cancer Research) described how very subtle changes to the imidazo[4,5-b]pyridine core could give fragments with wildly different selectivities. I was particularly tickled by his opening statement that he didn’t need to introduce the concept of fragment-based lead discovery in a general session on medicinal chemistry – another indication that FBLD is now mainstream.

Chris Johnson (Astex) told the story of their dual cIAP/XIAP inhibitor, a compound in preclinical development for cancer. As we’ve mentioned previously, most IAP inhibitors are peptidomimetics and are orders of magnitude more potent against cIAP than XIAP. Astex was looking for a molecule with similar potency against both targets. A fragment screen gave several good alanine-based fragments, as found in the natural ligand and most published inhibitors, but these were considerably more potent against cIAP. They also found a non-alanine fragment that was very weak (less than 20% inhibition at 5 mM!) but gave a well-defined crystal structure. The researchers were able to improve the affinity of this by more than six orders of magnitude, ultimately identifying compounds with low or sub-nanomolar activity in cells and only a 10-fold bias towards cIAP. This is a beautiful story that illustrates how important it is to choose a good starting point and not be lured solely by the siren of potency.

Alba Macias (Vernalis) talked about their efforts against the anti-cancer targets tankyrases 1 and 2 (we’ve previously written about this target here). In contrast to most fragment programs at Vernalis, this one started with a crystallographic screen, resulting in 62 structures (of 1563 fragments screened). Various SPR techniques, including off-rate screening, were used to prioritize and further optimize fragments, ultimately leading to sub-nanomolar compounds.

The debate over metrics and properties continued with back-to-back talks by Michael Shultz (Novartis) and Rob Young (GlaxoSmithKline). Michael gave an entertaining talk reprising some of his views (previously discussed here). I was happy to see that he does agree with the recent paper by Murray et al. that ligand efficiency is in fact mathematically valid; his previous criticism was based on use of the word “normalize” rather than “average”. While this is a legitimate point, it does smack of exegesis. Rob discussed the importance of minimizing molecular obesity and aromatic ring count and maximizing solubility, focusing on experimental (as opposed to calculated) properties. However, it is important to do the right kinds of measurements: Rob noted that log D values of greater than 4 are essentially impossible to measure accurately.

Of course, this was just a tiny fraction of the thousands of talks; if you heard something interesting please leave a comment.