Last week we highlighted work out of Agios leading to a clinical compound for the oncology target MAT2a. But given the appeal of new cancer targets, Agios is not without competition. In a recent (open access) J. Med. Chem. paper, Claudia De Fusco, Marianne Schimple, and colleagues at AstraZeneca describe their efforts.
The researchers started with fragment screens using thermal shift, crystallography, and SPR, with the latter providing the most potent and efficient hits. In particular, compounds 1 and 2 stood out and were subsequently found crystallographically to bind at the same allosteric site discussed last week. Interestingly, despite its higher affinity, compound 2 was inactive in a functional assay while compound 1 had an IC50 similar to its dissociation constant.
Initial efforts to improve the affinity of compound 1 were unsuccessful, but merging the two fragments yielded compound 5, which had comparable affinity to compound 2 and was also functionally active. Attempts to tweak the dimethylamine moiety were mostly unsuccessful, and a high-resolution (1.1 Å) crystal structure combined with quantum mechanical calculations revealed that the substituents around the aromatic quinazolinone ring system were twisted somewhat out of the plane.
Moving to the other side of the molecule, addition of the phenyl ring originally present in compound 2 gave a satisfying boost in affinity for compound 28, which was attributed in part to displacing two “unhappy” water molecules.
Compound 28 is active in cells and has good pharmacokinetics in rats. Unfortunately, it is cleared more rapidly in mice. Subcutaneous dosing in mouse xenograft models led to tumor stasis, though weight loss was also observed, suggesting toxicity. Though that likely precludes more intensive in vivo work, compound 28 could still be a useful chemical probe.
This paper is a nice example of fragment merging and growing. Notably, compound 28 is relatively small and very ligand efficient. Perhaps combining information from both this and the Agios series will lead to even better molecules.