TY - JOUR
T1 - Cyclin-dependent kinase inhibitor fadraciclib (CYC065) depletes anti-apoptotic protein and synergizes with venetoclax in primary chronic lymphocytic leukemia cells
AU - Chen, Rong
AU - Chen, Yuling
AU - Xiong, Ping
AU - Zheleva, Daniella
AU - Blake, David
AU - Keating, Michael J.
AU - Wierda, William G.
AU - Plunkett, William
N1 - Funding Information:
This study was supported in part by research funding from Cyclacel Pharmaceuticals to WP and RC, the CLL Global Research Foundation, generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots Program™, and a Cancer Center Support Grant CA016672 from the National Cancer Institute, Department of Health and Human Services. Fadraciclib was provided by Cyclacel Pharmaceuticals. The authors are thankful to Sarah Bronson from MD Anderson Research Medical Library for editing the paper.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/6
Y1 - 2022/6
N2 - Fadraciclib (CYC065) is a second-generation aminopurine CDK2/9 inhibitor with increased potency and selectivity toward CDK2 and CDK9 compared to seliciclib (R-roscovitine). In chronic lymphocytic leukemia (CLL), a disease that depends on the over-expression of anti-apoptotic proteins for its survival, inhibition of CDK9 by fadraciclib reduced phosphorylation of the C-terminal domain of RNA polymerase II and blocked transcription in vitro; these actions depleted the intrinsically short-lived anti-apoptotic protein Mcl-1 and induced apoptosis. While the simulated bone marrow and lymph node microenvironments induced Mcl-1 expression and protected CLL cells from apoptosis, these conditions did not prolong the turnover rate of Mcl-1, and fadraciclib efficiently abrogated the protective effect. Further, fadraciclib was synergistic with the Bcl-2 antagonist venetoclax, inducing more profound CLL cell death, especially in samples with 17p deletion. While fadraciclib, venetoclax, and the combination each had distinct kinetics of cell death induction, their activities were reversible, as no additional cell death was induced upon removal of the drugs. The best combination effects were achieved when both drugs were maintained together. Altogether, this study provides a rationale for the clinical development of fadraciclib in CLL, either alone or in combination with a Bcl-2 antagonist.
AB - Fadraciclib (CYC065) is a second-generation aminopurine CDK2/9 inhibitor with increased potency and selectivity toward CDK2 and CDK9 compared to seliciclib (R-roscovitine). In chronic lymphocytic leukemia (CLL), a disease that depends on the over-expression of anti-apoptotic proteins for its survival, inhibition of CDK9 by fadraciclib reduced phosphorylation of the C-terminal domain of RNA polymerase II and blocked transcription in vitro; these actions depleted the intrinsically short-lived anti-apoptotic protein Mcl-1 and induced apoptosis. While the simulated bone marrow and lymph node microenvironments induced Mcl-1 expression and protected CLL cells from apoptosis, these conditions did not prolong the turnover rate of Mcl-1, and fadraciclib efficiently abrogated the protective effect. Further, fadraciclib was synergistic with the Bcl-2 antagonist venetoclax, inducing more profound CLL cell death, especially in samples with 17p deletion. While fadraciclib, venetoclax, and the combination each had distinct kinetics of cell death induction, their activities were reversible, as no additional cell death was induced upon removal of the drugs. The best combination effects were achieved when both drugs were maintained together. Altogether, this study provides a rationale for the clinical development of fadraciclib in CLL, either alone or in combination with a Bcl-2 antagonist.
UR - http://www.scopus.com/inward/record.url?scp=85127717249&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85127717249&partnerID=8YFLogxK
U2 - 10.1038/s41375-022-01553-w
DO - 10.1038/s41375-022-01553-w
M3 - Article
C2 - 35383271
AN - SCOPUS:85127717249
SN - 0887-6924
VL - 36
SP - 1596
EP - 1608
JO - Leukemia
JF - Leukemia
IS - 6
ER -