LY2857785 was identified as a type I reversible and competitive ATP kinase inhibitor against CDK9 and other transcription kinases CDK8 and CDK7.[1,2]
Cdk7 acts as a Cdk-activating kinase and regulate transcription. Cdk8 and Cdk9 regulate transcription via phosphorylation of the RNA polymerase II carboxyl terminal domain. The Cdk9-related pathway performs an important role in several biological processes, such as cell growth, proliferation, protection from apoptosis and differentiation. These kinases are reported dys-regulation in some cancers. [2]
Transcription activation requires phosphorylation of a carboxyl-terminal domain, by a variety of kinases including CDK7, CDK8, and CDK9. By inhibiting these kinases, LY2857785 has unique transcription inhibitor activity. LY2857785 dramatically inhibited XIAP protein level in MV-4-11 and other hematologic cancer cells. It also can significantly reduce RNAP II CTD phosphorylation and dramatically decreases MCL1 protein levels to result in apoptosis in a variety of leukemia and solid tumor cell lines. [1]
LY2857785 potently inhibits a carboxyl-terminal domain phosphorylation and exhibits antitumor efficacy in orthotopic models of leukemia. LY2857785 inhibits the growth of leukemia cells, including orthotopic leukemia preclinical models as well as in ex vivo acute myeloid leukemia and chronic lymphocytic leukemia patient tumor samples. LY2857785 may be used in treating patients with hematologic tumors, particularly AML and CLL. [1]
References:
[1] Yin T, Lallena MJ, Kreklau EL etal. , A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models. Mol Cancer Ther. 2014 Jun;13(6):1442-56.
[2] Romano G1, Giordano A. Role of the cyclin-dependent kinase 9-related pathway in mammalian gene expression and human diseases. Cell Cycle. 2008 Dec;7(23):3664-8.