Abstract 1820: CDK3: A novel tumor-selective drug target involved in AP1 activation and transcriptional damage response
Authors: Porter Donald C. , Danes Christopher , Chang Bey-Dih , West Deborah , Altilia Serena , Friedhoff Lawrence T. , Lam Polo , Totrov Maxim , Abagyan Ruben , Lim Chang-uk , Broude Eugenia V. , Roninson Igor B. 
Published: August 2012

Cellular damage by chemotherapy or radiation induces transcriptional damage response that leads to increased production of tumor-promoting cytokines and decreases the treatment efficacy. The same response can be triggered by the overexpression of a damage-inducible cell cycle inhibitor p21 (Chang et al., PNAS 97, 4291, 2000 and PNAS 99, 389, 2002). High-throughput screening of diversified small-molecule libraries for the ability to prevent the induction of transcription in p21-expressing cells yielded a number of inhibitors of this transcriptional response. One of these compounds, designated SNX9, and a series of SNX9-related molecules, also showed unexpected cytotoxicity that was selective for tumor relative to normal cells. SNX9-class compounds strongly inhibited transcriptional activation of different tumor-promoting cytokines in irradiated colon cancer cells and potentiated the induction of apoptosis by doxorubicin and irinotecan. SNX9-class compounds showed tumoricidal activity against different tumor cell types in vitro and against colon carcinoma xenografts in vivo. Kinome profiling, followed by siRNA verification, identified the target of SNX9-class compounds as CDK3, a member of cyclin-dependent kinase (CDK) family. While CDK3 is closely related to cell cycle regulating kinase CDK2, it is not required for cell cycle progression in normal cells, judging by its spontaneous mutational inactivation in the germline of laboratory mice (Ye et al., PNAS 98, 1682, 2001) and very low expression in human tissues. CDK3, however, was reported to be overexpressed in tumor cells, where it displays oncogenic activity due to its ability to activate AP1 (Jun/Fos), a transcription factor involved in carcinogenesis (Zheng et al., Cancer Res., 68, 7650, 2008; Cho et al., Cancer Res., 69, 272, 2009). In agreement with these findings, AP1 was upregulated upon p21 expression and inhibited by SNX9-class CDK3 inhibitors. SNX9-class compounds inhibited CDK3 preferentially to CDK2 and other CDKs, despite the fact that the ATP pocket, the usual active site of kinase inhibitors, is highly conserved between CDK3 and CDK2. ATP competition assays revealed that SNX9-class compounds do not act at the ATP pocket, and molecular modeling suggested a novel allosteric binding pocket for these compounds, which is distinct between CDK3 and CDK2. Tumor-selective expression and function of CDK3 and its roles in AP1 activation, tumor cell survival and transcriptional damage response suggest this kinase as an exceptionally promising new target for cancer treatment.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1820. doi:1538-7445.AM2012-1820