Sometimes sticking to the unconventional pays off. In their efforts toward inhibitors of cyclin-dependent kinases (CDKs) as a new generation of anticancer drugs, Ulrich Lücking and researchers at the Bayer Research Center, Berlin, Germany, discovered a series of pan-CDK inhibitors based on an aminopyrimidine scaffold.

The first clinical candidate of this collaborative research effort, ZK 304709, failed in phase I studies due to dose-limited absorption and high inter-patient variability, which was attributed to limited aqueous solubility and off-target activity against carbonic anhydrases. Further lead optimization efforts addressing the off-target activity profile resulted in the introduction of a sulfoximine group. Interestingly, sulfoximines have limited precedent in medicinal chemistry, and their proposed use was met with a good deal of skepticism at first. However, the sulfoximine series of compounds soon revealed very interesting properties. The result of this effort culminated in the identification of the nanomolar pan-CDK inhibitor BAY 1000394 (pictured), which is currently being investigated in phase I clinical trials.

• The Lab Oddity Prevails: Discovery of Pan-CDK Inhibitor (R)-S-Cyclopropyl-S-(4-{[4-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulfoximide (BAY 1000394) for the Treatment of Cancer,
  U. Lücking, R. Jautelat, M. Krüger, T. Brumby, P. Lienau, M. Schäfer, H. Briem, J. Schulze, A. Hillisch, A. Reichel, G. Siemeister,
  ChemMedChem 2013, 9(07).
  DOI: 10.1002/cmdc.201300096