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Publication Abstract from PubMed

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 lab oddity prevails: discovery of pan-CDK inhibitor (R)-S-cyclopropyl-S-(4-{[4-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-(trifluorome thyl)pyrimidin-2-yl]amino}phenyl)sulfoximide (BAY 1000394) for the treatment of cancer.,Lucking U, Jautelat R, Kruger M, Brumby T, Lienau P, Schafer M, Briem H, Schulze J, Hillisch A, Reichel A, Wengner AM, Siemeister G ChemMedChem. 2013 Jul;8(7):1067-85. doi: 10.1002/cmdc.201300096. Epub 2013 May, 13. PMID:23671017^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.