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.
1 comment:
But how could they expect specificity if they didn't consider it during their elaboration?
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