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

Ulrich Lücking; Rolf Jautelat; Martin Krüger; Thomas Brumby; Philip Lienau; Martina Schäfer; Hans Briem; Julia Schulze; Alexander Hillisch; Andreas Reichel; Antje Margret Wengner; Gerhard Siemeister

doi:10.1002/cmdc.201300096

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

ChemMedChem. 2013 Jul;8(7):1067-85. doi: 10.1002/cmdc.201300096. Epub 2013 May 13.

Authors

Ulrich Lücking¹, Rolf Jautelat, Martin Krüger, Thomas Brumby, Philip Lienau, Martina Schäfer, Hans Briem, Julia Schulze, Alexander Hillisch, Andreas Reichel, Antje Margret Wengner, Gerhard Siemeister

Affiliation

¹ Bayer Pharma AG, Global Drug Discovery, Medicinal Chemistry, 13353 Berlin, Germany. ulrich.luecking@bayer.com

PMID: 23671017
DOI: 10.1002/cmdc.201300096

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.

MeSH terms

Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Cyclin-Dependent Kinases / antagonists & inhibitors*
Cyclin-Dependent Kinases / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Female
HeLa Cells
High-Throughput Screening Assays
Humans
Mice
Models, Molecular
Molecular Structure
Molecular Weight
Neoplasms, Experimental / drug therapy*
Neoplasms, Experimental / enzymology
Neoplasms, Experimental / metabolism
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / administration & dosage
Pyrimidines / chemical synthesis
Pyrimidines / pharmacology*
Rats
Structure-Activity Relationship
Sulfoxides / administration & dosage
Sulfoxides / chemical synthesis
Sulfoxides / pharmacology*
Uterine Cervical Neoplasms / drug therapy*
Uterine Cervical Neoplasms / enzymology
Uterine Cervical Neoplasms / metabolism

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
Sulfoxides
roniciclib
Cyclin-Dependent Kinases