A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models.
Mol Cancer Ther
; 13(6): 1442-56, 2014 Jun.
Article
in En
| MEDLINE
| ID: mdl-24688048
ABSTRACT
DNA-dependent RNA polymerase II (RNAP II) largest subunit RPB1 C-terminal domain (CTD) kinases, including CDK9, are serine/threonine kinases known to regulate transcriptional initiation and elongation by phosphorylating Ser 2, 5, and 7 residues on CTD. Given the reported dysregulation of these kinases in some cancers, we asked whether inhibiting CDK9 may induce stress response and preferentially kill tumor cells. Herein, we describe a potent CDK9 inhibitor, LY2857785, that significantly reduces RNAP II CTD phosphorylation and dramatically decreases MCL1 protein levels to result in apoptosis in a variety of leukemia and solid tumor cell lines. This molecule inhibits the growth of a broad panel of cancer cell lines, and is particularly efficacious in leukemia cells, including orthotopic leukemia preclinical models as well as in ex vivo acute myeloid leukemia and chronic lymphocytic leukemia patient tumor samples. Thus, inhibition of CDK9 may represent an interesting approach as a cancer therapeutic target, especially in hematologic malignancies.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Leukemia
/
Apoptosis
/
Cyclohexylamines
/
Cyclin-Dependent Kinase 9
/
Indazoles
/
Antineoplastic Agents
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Mol Cancer Ther
Journal subject:
ANTINEOPLASICOS
Year:
2014
Type:
Article
Affiliation country:
United kingdom