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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
Ist Teil von
ChemMedChem, 2013-07, Vol.8 (7), p.1067-1085
Ort / Verlag
Weinheim: WILEY-VCH Verlag
Erscheinungsjahr
2013
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
Lead optimization of a high‐throughput screening hit led to the rapid identification of aminopyrimidine ZK 304709, a multitargeted CDK and VEGF‐R inhibitor that displayed a promising preclinical profile. Nevertheless, 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 to address the off‐target activity profile finally resulted in the introduction of a sulfoximine group, which is still a rather unusual approach in medicinal chemistry. However, the sulfoximine series of compounds quickly revealed very interesting properties, culminating in the identification of the nanomolar pan‐CDK inhibitor BAY 1000394, which is currently being investigated in phase I clinical trials.
The unconventional proposal to introduce a sulfoximine group into a lead series of aminopyrimidine pan‐CDK inhibitors was initially met with much skepticism. However, it was the introduction of the sulfoximine group that finally allowed the project problems to be overcome, culminating in the identification of BAY 1000394, a nanomolar pan‐CDK inhibitor that is currently being investigated in phase I clinical trials.