Fragments vs MNK1 and MNK2: take three

Mitogen-activating protein kinase-interacting kinases 1 and 2, or MNK1 and MNK2, are implicated in several cancers while seeming to be dispensable for normal cells, making them attractive oncology targets. Indeed, we’ve previously written about two FBDD-derived clinical compounds against these kinases, eFT508 and ETC-206. In a J. Med. Chem. paper published last month, Alvin Hung and colleagues at A*STAR describe a third series.

The researchers started by screening 1700 fragments in a biochemical assay, resulting in 11 molecules that inhibited both MNK1 and MNK2 with decent ligand efficiency. Four of these had a meta-substituted pyridine, as in compound 6. Making a few analogs led to compound 13, with low micromolar potency against both enzymes.

Crystallography proved unsuccessful, but making the reasonable assumption that the pyridyl nitrogen binds to the kinase hinge region led to two models, only one of which was consistent with the SAR. Decoration of the phenyl ring led to compound 21, with submicromolar activity. Although still early, the researchers collected both in vitro and in vivo ADME data on this molecule, which turned out to be quite promising.

Next the researchers turned to the pyridyl ring and found that appending small (5-membered) heterocycles could also boost potency, as in compound 36. At this point, after multiple attempts with previous compounds, crystallography finally yielded a structure that confirmed the proposed binding mode. Combining elements from compounds 21 and 36 directly led to only a slight boost in activity, but further tweaking ultimately led to compound 47, the most potent member of the series. Unfortunately this molecule was unstable in mouse liver microsomes, but a related compound showed good mouse pharmacokinetics as well as impressive selectivity in a panel of 104 kinases.

No pharmacodynamic studies are described, and perhaps this series was deprioritized to focus on ETC-206, which was also developed at A*STAR. Indeed, the later compounds in this paper reveal a frustrating struggle between potency and stability often seen in medicinal chemistry. This is captured in a nice timeline that shows a rapid improvement in potency over about 8 months, followed by a slight drop as the researchers tried to improve exposure. Although no Goldilocks molecule is reported, this paper is nonetheless a lovely example of fragment to lead optimization done for the most part without the aid of crystallography.