2. Academic Validation
  3. A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models

A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models

  • Mol Cancer Ther. 2014 Jun;13(6):1442-56. doi: 10.1158/1535-7163.MCT-13-0849.
Tinggui Yin 1,  Maria J Lallena 1,  Emiko L Kreklau 1,  Kevin R Fales 1,  Santiago Carballares 1,  Raquel Torrres 1,  Graham N Wishart 1,  Rose T Ajamie 1,  Damien M Cronier 1,  Phillip W Iversen 1,  Timothy I Meier 1,  Robert T Foreman 1,  Douglas Zeckner 1,  Sean E Sissons 1,  Bart W Halstead 1,  Aimee B Lin 1,  Gregory P Donoho 1,  Yuewei Qian 1,  Shuyu Li 1,  Song Wu 1,  Amit Aggarwal 1,  Xiang S Ye 1,  James J Starling 1,  Richard B Gaynor 1,  Alfonso de Dios 2,  Jian Du 2
Affiliations

Affiliations

  • 1 Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom.
  • 2 Authors' Affiliations: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana; Eli Lilly and Company, Alcobendas, Madrid, Spain; and Eli Lilly and Company, Windlesham, United Kingdom du_jian@lilly.com de_dios_alfonso@lilly.com.
PMID: 24688048 DOI: 10.1158/1535-7163.MCT-13-0849
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.

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