title: Conformational Adaption May Explain the Slow Dissociation Kinetics of Roniciclib (BAY 1000394), a Type I CDK Inhibitor with Kinetic Selectivity for CDK2 and CDK9.
abstract: Roniciclib (BAY 1000394) is a type I pan-CDK (cyclin-dependent kinase) inhibitor which has revealed potent efficacy in xenograft cancer models. Here, we show that roniciclib displays prolonged residence times on CDK2 and CDK9, whereas residence times on other CDKs are transient, thus giving rise to a kinetic selectivity of roniciclib. Surprisingly, variation of the substituent at the 5-position of the pyrimidine scaffold results in changes of up to 3 orders of magnitude of the drug-target residence time. CDK2 X-ray cocrystal structures have revealed a DFG-loop adaption for the 5-(trifluoromethyl) substituent, while for hydrogen and bromo substituents the DFG loop remains in its characteristic type I inhibitor position. In tumor cells, the prolonged residence times of roniciclib on CDK2 and CDK9 are reflected in a sustained inhibitory effect on retinoblastoma protein (RB) phosphorylation, indicating that the target residence time on CDK2 may contribute to sustained target engagement and antitumor efficacy.
authors.affiliation: Bayer Pharma AG , Drug Discovery, Lead Discovery Berlin, Berlin, Germany.
authors.forename: Pelin
authors.initials: P
authors.lastname: Ayaz
authors.affiliation: Bayer Pharma AG , Drug Discovery, Lead Discovery Berlin, Berlin, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Andres
authors.affiliation: Bayer Pharma AG , Drug Discovery, Lead Discovery Berlin, Berlin, Germany.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Kwiatkowski
authors.affiliation: Bayer Pharma AG , Drug Discovery, Lead Discovery Berlin, Berlin, Germany.
authors.forename: Carl-Christian
authors.initials: CC
authors.lastname: Kolbe
authors.affiliation: Bayer Pharma AG , Drug Discovery, Research Pharmacokinetics, Berlin, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Lienau
authors.affiliation: Bayer Pharma AG , Drug Discovery, TRG Oncology, Berlin, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Siemeister
authors.affiliation: Bayer Pharma AG , Drug Discovery, Medicinal Chemistry, Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lücking
authors.affiliation: Bayer Pharma AG , Drug Discovery, Lead Discovery Berlin, Berlin, Germany.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Stegmann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors*; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D061986:MCF-7 Cells; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000493:pharmacokinetics; D013454:Sulfoxides / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: C515235:(4-amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl)(2,3-difluoro-6-methoxyphenyl)methanone; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D013454:Sulfoxides; C000622581:ZK 304709; C578610:roniciclib; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; C495893:Cdk2 protein, mouse; C467972:Cdk9 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D042863:Cyclin-Dependent Kinase 9