Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor.
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.
Parry
David
D
Merck Research Laboratory-Palo Alto, 901 California Avenue, Palo Alto, CA 94304-1104, USA. david.parry@merck.com
Guzi
Timothy
T
Shanahan
Frances
F
Davis
Nicole
N
Prabhavalkar
Deepa
D
Wiswell
Derek
D
Seghezzi
Wolfgang
W
Paruch
Kamil
K
Dwyer
Michael P
MP
Doll
Ronald
R
Nomeir
Amin
A
Windsor
William
W
Fischmann
Thierry
T
Wang
Yaolin
Y
Oft
Martin
M
Chen
Taiying
T
Kirschmeier
Paul
P
Lees
Emma M
EM
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
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