Fragments 2024

Last week saw the first of four dedicated fragment meetings this year: Fragments 2024, the 9^th RSC-BMCS Fragment-based Drug Discovery Meeting, was held in historic Hinxton Hall, Cambridge, UK. I won’t attempt to cover the 17 talks, 40+ posters, and 20 exhibitors in detail but just try to hit on some broad themes.

 

One highlight was a talk by Chris Swain, whose Cambridge MedChem Consulting has come up several times at Practical Fragments. Chris has been systematically cataloging fragment hits reported in the literature, and his database now includes >2500 fragments from >300 papers that hit 265 targets. This has not been easy: as we’ve noted in our annual F2L reviews, papers don’t always mention fragments in the title or abstract; sometimes you need to dig deep into the experimental methods to find out the origin of the initial hits, and even then there are questions of interpretation. Chris noted that the the drug aprepitat originated from a fragment-like pharamacophore extracted from a more complex literature compound. That story was published in 1998, predating the term “fragment-based drug discovery,” but perhaps it would be considered FBDD today.

 

The fragments themselves are a diverse bunch, with an average Tanimoto similarity of just 0.09, but there are small clusters. Looking at them in more detail, the ten most common scaffolds are aromatic (benzene, indole), which is a departure from approved drugs. There is also a significant fraction of charged molecules, including 298 acids and 348 basic groups. About 10% of the fragments hit more than one target, exactly what you would expect from the theory of molecular complexity.

 

Chris’s talk was followed by a wide-ranging panel discussion that expanded on some of these themes. Solubility was recognized as important, though with different techniques being more persnickety: Justin Dietrich (AbbVie) noted that pre-screening is critical for SPR, but for protein-detected NMR the protein is present at high enough concentrations to act as a “phase transfer reagent.”

 

The topic of thermodynamics also came up, with Chris Murray noting that Astex collects lots of ITC data but uses it for assessing free energy (ΔG) values rather than enthalpic energy (ΔH) values. Helena Danielson (Uppsala University) noted that the early correlation between compound quality and enthalpy found with HIV protease inhibitors did not seem to apply to other targets despite significant investment in collecting data at multiple companies, as also noted by Chris Smith (Mirati) and Mike Hann (GSK). Rod Hubbard (Vernalis) puckishly suggested that the study of ΔH had produced “more heat than light.”

 

The topic of MiniFrags also came up during the panel discussion. Chris Murray noted that they had been tried on quite a few targets but, as Rod Hubbard confirmed, were more helpful in identifying binding sites than providing starting points. But Chris Smith pronounced himself a “complete convert” after a MiniFrag identified an induced pocket on a previously intractable target where fragments (and other techniques) had failed.

 

Covalent fragments also made several appearances, with Jonathan Pettinger describing a phenotypic screen at GSK looking for compounds that block the pro-inflammatory M1 polarization of macrophages. After screening some 2000 covalent fragments they used chemoproteomics to determine that one of the best compounds acted by modifying cysteine 817 of the kinase JAK1. Interestingly, this is the same cysteine identified independently by researchers from Vividion, which could speak to the centrality of this target, the reactivity of this particular cysteine, or both.

 

Pursuing residues other than cysteine is seen as difficult, with Mike Hann noting in the panel discussion that these may require more extensive non-covalent interactions and Chris Murray noting that the warheads themselves were less attractive. But these challenges have not dissuaded Peter Cossar (Eindoven University of Technology), who has introduced cysteine-reactive disulfide and lysine-reactive aldehyde moieties into the same fragment to crosslink a 14-3-3 protein to substrate ERRγ.

 

Another theme was screening crude reaction mixtures in a “direct to biology” approach. Vernalis was an early adopter with their off-rate screening, and a talk by Lucie Guetzoyan confirmed that they are continuing to invest here not just with SPR but also with affinity-selection mass spectrometry and X-ray crystallography. Lucie also described using flow chemistry to enable sensitive organometallic chemistries such as Grignard and Negishi couplings. John Spencer (University of Sussex) is also using crude reaction screening by crystallography and thought the approach can compress ten years worth of work into a few months.

 

As with most conferences these days there were plenty of success stories. Martina Schaefer (Nuvisan) described the discovery of the Bayer SOS1 inhibitor BAY-293, which we wrote about here. Anna Vulpetti (Novartis) described the discovery of IL-1β inhibitors, which we wrote about here. Nicola Wilsher (Astex) described the discovery of potent SHP2 inhibitors; I’ll write more about these later. And Matthew Calabrese described the discovery of allosteric activators selective for the γ3 subunit of AMPK, which could avoid the cardiotoxicity seen with less selective molecules. Three HTS screens had failed but fragments ultimately led to a potent tool molecule. Interestingly, some of the HTS compounds were later found to be hits but had been overlooked because they were so weak that they did not rise above the noise of the assay.

 

Finally, Justin Dietrich described several success stories, including against TNFα (which we wrote about here) as well as CD40 ligand. Justin noted that FBLD is used alongside HTS and DEL at AbbVie, and that the techniques can be complementary – a theme noted by several others.

 

Despite being so intimately integrated with other discovery approaches, FBLD continues to innovate and evolve and remain sufficiently quirky that stand-alone meetings are still valuable and rewarding. I’m looking forward to seeing what the next several meetings reveal.