title: 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.
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.
authors.affiliation: Bayer Pharma AG, Global Drug Discovery, Medicinal Chemistry, 13353 Berlin, Germany. ulrich.luecking@bayer.com
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lücking
authors.forename: Rolf
authors.initials: R
authors.lastname: Jautelat
authors.forename: Martin
authors.initials: M
authors.lastname: Krüger
authors.forename: Thomas
authors.initials: T
authors.lastname: Brumby
authors.forename: Philip
authors.initials: P
authors.lastname: Lienau
authors.forename: Martina
authors.initials: M
authors.lastname: Schäfer
authors.forename: Hans
authors.initials: H
authors.lastname: Briem
authors.forename: Julia
authors.initials: J
authors.lastname: Schulze
authors.forename: Alexander
authors.initials: A
authors.lastname: Hillisch
authors.forename: Andreas
authors.initials: A
authors.lastname: Reichel
authors.forename: Antje Margret
authors.initials: AM
authors.lastname: Wengner
authors.forename: Gerhard
authors.initials: G
authors.lastname: Siemeister
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005260:Female; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013454:Sulfoxides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013454:Sulfoxides; C578610:roniciclib; D018844:Cyclin-Dependent Kinases