Faculty, Staff and Student Publications
Publication Date
6-1-2022
Journal
Leukemia
Abstract
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.
Keywords
Adenosine, Apoptosis, Apoptosis Regulatory Proteins, Bridged Bicyclo Compounds, Heterocyclic, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Myeloid Cell Leukemia Sequence 1 Protein, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-bcl-2, Roscovitine, Sulfonamides, Tumor Microenvironment
DOI
10.1038/s41375-022-01553-w
PMID
35383271
PMCID
PMC9162916
PubMedCentral® Posted Date
4-5-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Hematology Commons, Hemic and Lymphatic Diseases Commons, Medical Genetics Commons, Oncology Commons