CDK3-inhibiting anticancer agents

DESCRIPTION (provided by applicant): This Phase II SBIR project is aimed at developing a novel type of drugs, termed SNX9-class compounds, with a unique combination of two anticancer activities. The first is a selective antiproliferative effect on tumor cells relative to normal cells. The second is the inhibition of chemotherapy- or radiation-induced expression of multiple genes encoding secreted tumor-supporting factors with mitogenic, antiapoptotic and angiogenic activities; as a result, SNX9-class compounds potentiate the induction of apoptosis by conventional chemotherapeutic drugs. Studies conducted during Phase I of this project showed that both activities of SNX9- class compounds are due to their ability to inhibit CDK3. This understudied member of the cyclin-dependent kinase (CDK) family is apparently unneeded by normal cells, based on its very low expression in normal human tissues and spontaneous germline inactivation in laboratory mice. However, CDK3 is overexpressed in different cancers, where itacts as an oncogene enhancing the activity of transcription factor AP1 (Jun/Fos). This tumor selectivity advantageously distinguishes CDK3 as a cancer target from cell cycle-regulating CDKs (CDK1, CDK2, CDK4/6), which are targeted by pharmaceutical CDK inhibitors, previously developed by others. Computer modeling and structure-activity analysis conducted during Phase I indicate that SNX9-class compounds selectively inhibit CDK3 through binding to a newly identified allosteric pocket that distinguishes CDK3from the closely related CDK2 and other CDKs. The first aim of the proposed Phase II study is to develop new, more potent and selective SNX9-class CDK3 inhibitors through rational drug design, based on computer modeling of SNX9-CDK3 interactions. The second aim is to test the effects of SNX9-class compounds on the production of multiple tumor-supporting secreted factors by chemotherapy- and radiation- damaged tumor cells, at the levels of RNA, protein, and paracrine anti-apoptotic activity. The third aim isto test SNX9-class compounds for their antiproliferative activity in different colon carcinoma and glioblastoma cell lines, the tumor types that are indicated by CDK3 expression and inhibition assays to be most likely to be susceptible to CDK3 inhibitors.The fourth aim is to evaluate SNX9-class compounds that show in vitro potency and CDK3 selectivity by assessments of in vivo toxicity and pharmacokinetics in rats (which, unlike laboratory mice, express functional CDK3). The results of these assessments will be used to select the compound with the most favorable pharmacokinetics and the least toxicity for in vivo efficacy studies, which constitute the fifth and the final aim of this proposal. In vivo tumor-suppression studies will be conducted in rat xenograft models of human colon carcinoma and glioblastoma (intracranial model). A compound showing safety and efficacy in vivo will be selected for preclinical and clinical development as a new anticancer drug. PUBLIC HEALTH RELEVANCE: The goal of thisPhase II SBIR project is to develop a novel type of drug with a unique combination of two anticancer activities: selective killing of tumor cells and increasing the effect of existing anticancer drugs. Both of these activities are mediated through the inhibition of a protein CDK3, which is not needed by normal cells but plays an essential role in cancers. In the proposed program, improved CDK3 inhibitors will be developed through computer modeling and chemical synthesis and tested for activity against coloncancer and an intractable brain tumor glioblastoma.