The Lab Oddity Prevails: Discovery of Pan‐CDK Inhibitor (<i>R</i>)‐<i>S</i>‐Cyclopropyl‐<i>S</i>‐(4‐{[4‐{[(1<i>R</i>,2<i>R</i>)‐2‐hydroxy‐1‐methylpropyl]oxy}‐5‐(trifluoromethyl)pyrimidin‐2‐yl]amino}phenyl)sulfoximide (BAY 1000394) for the Treatment of Cancer

Abstract

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.