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The Lab Oddity Prevails: Discovery of Pan‐CDK Inhibitor ( R )‐ S ‐Cyclopropyl‐ S ‐(4‐{[4‐{[(1 R ,2 R )‐2‐hydroxy‐1‐methylpropyl]oxy}‐5‐(trifluoromethyl)pyrimidin‐2‐yl]amino}phenyl)sulfoximide (BAY 1000394) for the Treatment of Cancer
Author(s) -
Lücking Ulrich,
Jautelat Rolf,
Krüger Martin,
Brumby Thomas,
Lienau Philip,
Schäfer Martina,
Briem Hans,
Schulze Julia,
Hillisch Alexander,
Reichel Andreas,
Wengner Antje Margret,
Siemeister Gerhard
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300096
Subject(s) - chemistry , cyclin dependent kinase , solubility , drug discovery , cdk inhibitor , lead compound , pharmacology , computational biology , combinatorial chemistry , biochemistry , medicine , biology , in vitro , organic chemistry , gene , cell cycle
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.