The cyclin-dependent kinases (CDKs) are targets for a variety of diseases, particularly cancers. One of the earliest posts at Practical Fragments discussed the clinical-stage AT7519, which inhibits several CDKs. A new paper in Bioorg. Med. Chem. Lett. by Xingchun Han, Song Yang, and their colleagues at Roche Innovation Center Shanghai describes the discovery of a selective CDK8 inhibitor.
The researchers started with a biochemical screen (at 100 µM) of ~6500 fragments, all with less than 19 non-hydrogen atoms. A whopping 403 compounds showed >70% inhibition, and of 227 tested in full dose-response curves, 48 had IC50 < 50 µM with ligand efficiency > 0.3 kcal/mol/atom. Compound 1 was both potent and structurally interesting.
SAR by catalog led to several more active analogs, including compound 4, which was crystallographically characterized bound to CDK8 (blue). The pyridine nitrogen makes a hydrogen bond with the hinge-region of the kinase, while the pyrrole nitrogen makes a water-mediated bond to the protein. Interestingly though, benzylation of the pyrrole slightly improved affinity, suggesting that the molecule can bind in a flipped orientation, with the pyrrole nitrogen pointing out towards solvent. This binding mode would provide easy access to a small hydrophobic pocket, a hypothesis that was supported when compound 17 showed a dramatic increase in affinity. A crystal structure of compound 17 bound to CDK8 confirmed the flipped binding mode.
A closely related molecule (replacing the chlorine atom with a trifluoromethyl group) showed oral bioavailability and good pharmacokinetics in mice. And another closely related compound (methyl instead of chlorine) showed excellent selectivity against a panel of 43 kinases.