title: Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor.
abstract: Cyclin-dependent kinases (CDK) are key positive regulators of cell cycle progression and attractive targets in oncology. SCH 727965 inhibits CDK2, CDK5, CDK1, and CDK9 activity in vitro with IC(50) values of 1, 1, 3, and 4 nmol/L, respectively. SCH 727965 was selected as a clinical candidate using a functional screen in vivo that integrated both efficacy and safety parameters. Compared with flavopiridol, SCH 727965 exhibits superior activity with an improved therapeutic index. In cell-based assays, SCH 727965 completely suppressed retinoblastoma phosphorylation, which correlated with apoptosis onset and total inhibition of bromodeoxyuridine incorporation in >100 tumor cell lines of diverse origin and background. Moreover, short exposures to SCH 727965 were sufficient for long-lasting cellular effects. SCH 727965 induced regression of established solid tumors in a range of mouse models following intermittent scheduling of doses below the maximally tolerated level. This was associated with modulation of pharmacodynamic biomarkers in skin punch biopsies and rapidly reversible, mechanism-based effects on hematologic parameters. These results suggest that SCH 727965 is a potent and selective CDK inhibitor and a novel cytotoxic agent.
authors.affiliation: Merck Research Laboratory-Palo Alto, 901 California Avenue, Palo Alto, CA 94304-1104, USA. david.parry@merck.com
authors.forename: David
authors.initials: D
authors.lastname: Parry
authors.forename: Timothy
authors.initials: T
authors.lastname: Guzi
authors.forename: Frances
authors.initials: F
authors.lastname: Shanahan
authors.forename: Nicole
authors.initials: N
authors.lastname: Davis
authors.forename: Deepa
authors.initials: D
authors.lastname: Prabhavalkar
authors.forename: Derek
authors.initials: D
authors.lastname: Wiswell
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Seghezzi
authors.forename: Kamil
authors.initials: K
authors.lastname: Paruch
authors.forename: Michael P
authors.initials: MP
authors.lastname: Dwyer
authors.forename: Ronald
authors.initials: R
authors.lastname: Doll
authors.forename: Amin
authors.initials: A
authors.lastname: Nomeir
authors.forename: William
authors.initials: W
authors.lastname: Windsor
authors.forename: Thierry
authors.initials: T
authors.lastname: Fischmann
authors.forename: Yaolin
authors.initials: Y
authors.lastname: Wang
authors.forename: Martin
authors.initials: M
authors.lastname: Oft
authors.forename: Taiying
authors.initials: T
authors.lastname: Chen
authors.forename: Paul
authors.initials: P
authors.lastname: Kirschmeier
authors.forename: Emma M
authors.initials: EM
authors.lastname: Lees
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003497:Cyclic N-Oxides; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007212:Indolizines; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D005419:Flavonoids; D007212:Indolizines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011726:Pyridinium Compounds; D016160:Retinoblastoma Protein; C077990:alvocidib; C553669:dinaciclib; D011065:Poly(ADP-ribose) Polymerases; D018844:Cyclin-Dependent Kinases