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Data from Dinaciclib (SCH 727965), a Novel and Potent Cyclin-Dependent Kinase Inhibitor
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Data from Dinaciclib (SCH 727965), a Novel and Potent Cyclin-Dependent Kinase Inhibitor
Data from Dinaciclib (SCH 727965), a Novel and Potent Cyclin-Dependent Kinase Inhibitor
DP
David Parry
David Parry
TG
Timothy Guzi
Timothy Guzi
FS
Frances Shanahan
Frances Shanahan
ND
Nicole Davis
Nicole Davis
DP
Deepa Prabhavalkar
Deepa Prabhavalkar
DW
Derek Wiswell
Derek Wiswell
WS
Wolfgang Seghezzi
Wolfgang Seghezzi
KP
Kamil Paruch
Kamil Paruch
MD
Michael P. Dwyer
Michael P. Dwyer
RD
Ronald Doll
Ronald Doll
AN
Amin Nomeir
Amin Nomeir
WW
William Windsor
William Windsor
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31 March 2023
other
Published by
American Association for Cancer Research (AACR)
https://doi.org/10.1158/1535-7163.c.6532211.v1
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 IC50 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. Mol Cancer Ther; 9(8); 2344–53. ©2010 AACR.
Keywords
SCH
APOPTOSIS
PHOSPHORYLATION
CYCLIN
KINASES
INHIBITOR
DIVERSE
EFFICACY
SAFETY
TOLERATED
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