Abstract PR08: Targeting tumor microenvironment with selective small-molecule inhibitors of CDK8/19 (2015)

Abstract Cyclin-dependent kinase 8 (CDK8), along with its closely related paralog CDK19, are transcription-regulating kinases that, unlike some other members of the CDK family, do not regulate cell cycle progression and are not required for the growth of normal cells or most of the tumor cell types. CDK8 has been identified as an oncogene that enhances the activity of several tumor-promoting transcriptional pathways (such as TGFβ, β-catenin, HIF1A and serum factors), mediating the elongation of transcription of newly activated genes. We have previously reported the discovery of the first selective small-molecule inhibitors of CDK8/19 and their ability to block chemotherapy-induced tumor-promoting paracrine activities of both tumor and normal cells (Porter et al., PNAS 109, 13799, 2012). We now conducted chemical optimization of the original inhibitors, yielding an optimized preclinical lead compound, Senexin B. Senexin B inhibits CDK8/19 in low nanomolar range in vitro and in vivo as an ATP pocket binder, with very high target selectivity as indicated by kinome profiling. It is highly water-soluble, bioavailable, and produces no limiting toxicity upon prolonged administration in mice, at doses that yield plasma concentrations exceeding cellular IC50 by 2-3 orders of magnitude. Senexin B has been tested for efficacy in several animal models addressing different aspects of tumor growth and progression. (i) Pretreatment of tumor-free mice with Senexin B significantly inhibited the growth of triple-negative breast cancer (TNBC) cells inoculated into mice subsequently to Senexin B administration, indicating a general chemopreventive effect on the normal tissue “soil”. (ii) Senexin B potentiated the tumor-suppressive effect of doxorubicin on established TNBC xenografts; this effect was associated with the suppression of NFκB-mediated transcriptional induction of tumor-promoting cytokines. (iii) Senexin B inhibited invasive growth into the muscle layer in an orthotopic xenograft model of MDA-MB-468 TNBC cells. (iv) In a spleen-to-liver colon cancer metastasis model of syngeneic mouse CT26 tumors, Senexin B treatment of mice had the same effect as CDK8 knockdown in tumor cells: suppression of metastatic growth in the liver without a significant effect on primary tumor growth in the spleen. Taken together, these results indicate that CDK8/19 inhibition produces chemopotentiating, chemopreventive and anti-metastatic effects in different types of cancer, inhibiting tumor progression by acting both at the tumor cells (the “seed”) and the tumor microenvironment (the “soil”) of cancers. Citation Format: Donald C. Porter, Mengqian Chen, Jiaxin Liang, Vimala Kaza, Alexander Chumanevich, Serena Altilia, Elena Farmaki, Marj Pena, Gary P. Schools, Ioulia Chatzistamou, Lawrence T. Friedhoff, Mark P. Wentland, Eugenia V. Broude, Hippokratis Kiaris, Igor B. Roninson. Targeting tumor microenvironment with selective small-molecule inhibitors of CDK8/19. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr PR08. doi:10.1158/1538-7445.CHTME14-PR08