Mitogen Activated Protein Kinase Kinase Kinase Kinase 4, or MAP4K4, is one of the 500+ human kinases that doesn’t get a whole lot of attention, in part perhaps because there aren’t many good tool compounds out there. A new paper from Genentech in Bioorg. Med. Chem. Lett. reports an attempt to change this.
The researchers started with a surface plasmon resonance (SPR) screen of 2361 fragments, yielding 225 confirmed hits with KD values between 10 and 2010 µM, all with ligand efficiency (LE) values above 0.3 kcal/mol/atom. This seems like a good use of LE: with hundreds of hits to choose from, some sort of triage is necessary, and you might as well go with those with the highest LE.
Compound 1 had moderate potency and excellent LE, as well as a structure familiar from other kinase programs. Modeling suggested growing off the amine, and a small set of compounds were made including compound 7, which gave a 10-fold boost in potency, albeit with a loss in LE. Crystallography of a close analog of compound 7 revealed that it bound as expected, and also suggested a fragment growing approach.
A number of substituents were introduced, all with an eye towards keeping lipophilicity low (clogD < 3.5). Compound 16 was the most potent, though the solubility was poor, and adding polar substituents didn’t help much. Compound 25 had similar potency, and in this case adding a polar substituent (compound 44) improved solubility too. The PK profile in mice was also reasonable.
Unfortunately, when tested at 1 µM against 63 kinases, compound 44 inhibited 16 of them by at least 75%, suggesting that it will not make a useful tool compound. The team reported better selectivity earlier this year with a series of compounds derived from a different fragment hit identified in the same SPR screen. Yet despite the outcome, this is a nice case study in using ligand efficiency, calculated hydrophobicity, and structural information to guide fragment growing.