Identification of Atuveciclib (BAY 1143572), the First Highly Selective, Clinical PTEFb/CDK9 Inhibitor for the Treatment of Cancer

Ulrich Lücking; Arne Scholz; Philip Lienau; Gerhard Siemeister; Dirk Kosemund; Rolf Bohlmann; Hans Briem; Ildiko Terebesi; Kirstin Meyer; Katja Prelle; Karsten Denner; Ulf Bömer; Martina Schäfer; Knut Eis; Ray Valencia; Stuart Ince; Franz von Nussbaum; Dominik Mumberg; Karl Ziegelbauer; Bert Klebl; Axel Choidas; Peter Nussbaumer; Matthias Baumann; Carsten Schultz-Fademrecht; Gerd Rühter; Jan Eickhoff; Michael Brands

doi:10.1002/cmdc.201700447

Identification of Atuveciclib (BAY 1143572), the First Highly Selective, Clinical PTEFb/CDK9 Inhibitor for the Treatment of Cancer

ChemMedChem. 2017 Nov 8;12(21):1776-1793. doi: 10.1002/cmdc.201700447. Epub 2017 Oct 16.

Authors

Ulrich Lücking¹, Arne Scholz¹, Philip Lienau¹, Gerhard Siemeister¹, Dirk Kosemund¹, Rolf Bohlmann¹, Hans Briem¹, Ildiko Terebesi¹, Kirstin Meyer¹, Katja Prelle¹, Karsten Denner¹, Ulf Bömer¹, Martina Schäfer¹, Knut Eis¹, Ray Valencia¹, Stuart Ince¹, Franz von Nussbaum¹, Dominik Mumberg¹, Karl Ziegelbauer¹, Bert Klebl², Axel Choidas², Peter Nussbaumer², Matthias Baumann², Carsten Schultz-Fademrecht², Gerd Rühter², Jan Eickhoff², Michael Brands¹

Affiliations

¹ Bayer AG, Pharmaceuticals Division, Drug Discovery, Müllerstr. 178, 13353, Berlin, Germany.
² Lead Discovery Center GmbH (LDC), Otto-Hahn-Str. 15, 44227, Dortmund, Germany.

Abstract

Selective inhibition of exclusively transcription-regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY-958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAY 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAY 1143572 exhibited the best overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats. BAY 1143572 is the first potent and highly selective PTEFb/CDK9 inhibitor to enter clinical trials for the treatment of cancer.

Keywords: CDK; PTEFb; antitumor agents; drug design; sulfoximines.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Binding Sites
Cell Line, Tumor
Cell Survival / drug effects
Crystallography, X-Ray
Cyclin-Dependent Kinase 9 / antagonists & inhibitors*
Cyclin-Dependent Kinase 9 / metabolism
Half-Life
HeLa Cells
Humans
Leukemia, Myeloid, Acute / drug therapy
Mice
Mice, Nude
Molecular Conformation
Molecular Docking Simulation
Neoplasms / drug therapy*
Neoplasms / pathology
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / therapeutic use*
Protein Kinase Inhibitors / toxicity
Protein Structure, Tertiary
Rats
Rats, Nude
Structure-Activity Relationship
Sulfonamides / chemistry
Sulfonamides / therapeutic use*
Sulfonamides / toxicity
Transplantation, Heterologous
Triazines / chemistry
Triazines / therapeutic use*
Triazines / toxicity

Substances

Protein Kinase Inhibitors
Sulfonamides
Triazines
atuveciclib
Cyclin-Dependent Kinase 9