PDB 3ET7 deposited: 2008-10-07 modified: 2009-06-23
Title Crystal structure of PYK2 complexed with PF-2318841
Authors Aspnes, G.E., Autry, C.L., Bauman, J.N., Bi, F.C., Bonnette, P.C., Buckbinder, L., Cooper, B.A., Dunn, M., Griffor, M.C., Guzman-Perez, A., Han, S., Hulford, C.A., Kalgutkar, A.S., Kath, J.C., Klug-McLeod, J., Kung, D.W., Li, J.C., Luzzio, M.J., McGlynn, M.A., Mistry, A., Oliver, R., Richter, D.T., Roberts, W.G., Soglia, J.R., Ung, E.J., Walker, D.P., Zawistoski, M.P., Zhao, S.X.
Structure factors resolution 2.7 rfactor 0.24664 rfree 0.3283
DPI 1.31 theoretical min: 0.56

The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay.

Bioorg.Med.Chem.Lett. 2008 Dec; 18(23):6071-6077 doi:10.1016/j.bmcl.2008.10.030

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL1152158
PubMed 18951788 BMCLE8
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3ET7/0 3ET7 0 monomer 0 1 2 1934