A Novel CDK9 Inhibitor Shows Potent Antitumor Efficacy in Preclinical Hematologic Tumor Models

作者：Yin Tinggui; Lallena Maria J; Kreklau Emiko L; Fales Kevin R; Carballares Santiago; Torrres Raquel; Wishart Graham N; Ajamie Rose T; Cronier Damien M; Iversen Phillip W; Meier Timothy I; Foreman Robert T; Zeckner Douglas; Sissons Sean E; Halstead Bart W; Lin Aimee B; Donoho Gregory P; Qian Yuewei; Li Shuyu; Wu Song; Aggarwal Amit; Ye Xiang S; Starling James J; Gaynor Richard B; de Dios Alfonso; Du Jian^*

来源：Molecular Cancer Therapeutics, 2014, 13(6): 1442-1456.

DOI：10.1158/1535-7163.MCT-13-0849

DNA-dependent RNA polymerase II (RNAP II) largest subunit RPB1 C-terminal domain (CTD) kinases, includingCDK9, 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.

• 出版日期2014-6