Design and synthesis of stabilized pironetin analogs for the treatment of resistant ovarian cancers

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 DESCRIPTION (provided by applicant) The American Cancer Society estimates that in 2015 more than 21,290 women will be diagnosed with ovarian epithelial cancer and that the five-year survival rate will be less than 50%. The National Cancer Institute estimates that 80% of ovarian epithelial cancer patients relapse following first-line platinum- and taxane-based chemotherapy. Nikas and coworkers have shown that the gene encoding α-tubulin, TUBA3C, is overexpressed in short-term ovarian cancer survivors following first-line chemotherapy. Drugs that alter microtubule dynamics are some of the most successful anticancer agents, however all tubulin-binding agents currently approved by the FDA target β-tubulin and are associated with drug resistance. Given the overall success of tubulin-binding anticancer agents, α-tubulin is an attractive alternative drug target that would address the critical need for new treatments for taxane and platinum drug resistant ovarian cancers. The natural product pironetin was identified as a potent antiproliferative agent with low nanomolar GI50 values against resistant ovarian carcinoma cell lines. It was determined that pironetin covalently binds to Lys352 of α-tubulin. While pironetin displays potent in vitro activity, the only reported in vivo study resulted in modest activity accompanied by severe weight loss, suggesting that pironetin has very poor pharmacokinetic/pharmacodynamic properties and possible off-target binding. This fellowship proposal will test the hypothesis that rapid metabolism of pironetin inhibits in vivo efficacy and synthetically blocking the sites of metabolism and developing a tumor-targeting approach will generate therapeutic agents with improved PK/PD properties. Methods include synthesizing and evaluating analogs of pironetin in cell based assays using cells both sensitive and resistant to current therapeutics (Aim 1), establishing a proof-of-concept antibody-pironetin conjugate (Aim 2), and evaluating analogs and conjugates in vivo (Aim 3). This proposed work will help to achieve the long-term goal of developing novel therapeutics that will be effective against resistant ovarian cancers. The objective of this proposal is to demonstrate that α-tubulin is a viable target for resistant ovarin cancers by synthesizing analogs and antibody-drug conjugates of pironetin that can be used to further understand the role of α-tubulin in ovarian cancer. This goal is aligned with the mission f the NIH to support research aimed at developing state-of-the-art treatments for cancer and other diseases.