TY - JOUR
T1 - Cyclin-dependent kinase inhibitor therapy for hematologic malignancies
AU - Bose, Prithviraj
AU - Simmons, Gary L.
AU - Grant, Steven
N1 - Funding Information:
This work was supported in part by the following awards to Grant: R01 CA093738, R01 CA167708, P50 CA130805, P50 CA142509, RC2 CA148431 from the National Institutes of Health, and an award from the Multiple Myeloma
PY - 2013/6
Y1 - 2013/6
N2 - Introduction: Cyclin-dependent kinases (CDKs) regulate cell cycle progression. Certain CDKs (e.g., CDK7, CDK9) also control cellular transcription. Consequently, CDKs represent attractive targets for anticancer drug development, as their aberrant expression is common in diverse malignancies, and CDK inhibition can trigger apoptosis. CDK inhibition may be particularly successful in hematologic malignancies, which are more sensitive to inhibition of cell cycling and apoptosis induction. Areas covered: A number of CDK inhibitors, ranging from pan-CDK inhibitors such as flavopiridol (alvocidib) to highly selective inhibitors of specific CDKs (e.g., CDK4/6), such as PD0332991, that are currently in various phases of development, are profiled in this review. Flavopiridol induces cell cycle arrest, and globally represses transcription via CDK9 inhibition. The latter may represent its major mechanism of action via down-regulation of multiple short-lived proteins. In early phase trials, flavopiridol has shown encouraging efficacy across a wide spectrum of hematologic malignancies. Early results with dinaciclib and PD0332991 also appear promising. Expert opinion: In general, the antitumor efficacy of CDK inhibitor monotherapy is modest, and rational combinations are being explored, including those involving other targeted agents. While selective CDK4/6 inhibition might be effective against certain malignancies, broad-spectrum CDK inhibition will likely be required for most cancers.
AB - Introduction: Cyclin-dependent kinases (CDKs) regulate cell cycle progression. Certain CDKs (e.g., CDK7, CDK9) also control cellular transcription. Consequently, CDKs represent attractive targets for anticancer drug development, as their aberrant expression is common in diverse malignancies, and CDK inhibition can trigger apoptosis. CDK inhibition may be particularly successful in hematologic malignancies, which are more sensitive to inhibition of cell cycling and apoptosis induction. Areas covered: A number of CDK inhibitors, ranging from pan-CDK inhibitors such as flavopiridol (alvocidib) to highly selective inhibitors of specific CDKs (e.g., CDK4/6), such as PD0332991, that are currently in various phases of development, are profiled in this review. Flavopiridol induces cell cycle arrest, and globally represses transcription via CDK9 inhibition. The latter may represent its major mechanism of action via down-regulation of multiple short-lived proteins. In early phase trials, flavopiridol has shown encouraging efficacy across a wide spectrum of hematologic malignancies. Early results with dinaciclib and PD0332991 also appear promising. Expert opinion: In general, the antitumor efficacy of CDK inhibitor monotherapy is modest, and rational combinations are being explored, including those involving other targeted agents. While selective CDK4/6 inhibition might be effective against certain malignancies, broad-spectrum CDK inhibition will likely be required for most cancers.
KW - Alvocidib
KW - Cyclin-dependent kinase inhibitors
KW - Dinaciclib
KW - Flavopiridol
KW - Mcl-1
KW - PD0332991
KW - Roscovitine
KW - SCH727965
KW - Seliciclib
KW - Targeted therapies
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U2 - 10.1517/13543784.2013.789859
DO - 10.1517/13543784.2013.789859
M3 - Review article
C2 - 23647051
AN - SCOPUS:84878252263
SN - 1354-3784
VL - 22
SP - 723
EP - 738
JO - Expert Opinion on Investigational Drugs
JF - Expert Opinion on Investigational Drugs
IS - 6
ER -