Multidisciplinary Investigation of Antitubulin Heterocycles using Synthesis, Biology, and Structural Analysis

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Tubulin is a protein involved in microtubule function, including mitosis, cell shape, migration, and movement of organelles. Tubulin inhibitors are used in cancer treatments; however, the current inhibitors tend to be complex molecules, and suffer from toxicity issues, multi-drug resistance, low solubility, and/or the lack of multi-cancer efficacy. The overall and long-term goal of this proposal is to use hypothesis-driven rational drug design to develop novel heterocyclic tubulin polymerization inhibitors. Using a robust, interdisciplinary mentoring research program with undergraduate researchers, we previously developed PY-407-C, a furanone-containing molecule that prevented tubulin polymerization and had nanomolar toxicity on cancer cells. Our 3 independent but complementary goals are as follows. First, we will characterize previously identified PY molecules for (a) tubulin binding by molecular modeling, (b) concentration needed to inhibit tubulin polymerization compared to known inhibitors, and (c) binding to non-tubulin proteins in order to assess specificity. Second, we will employ rational drug design to identify new heterocyclic tubulin inhibitors via a hypothesis-driven, multi-disciplinary rational drug design loop of (1) modeling, (2) from which we will design and synthesize new furanone-based targets, and (3) assay the resultant compounds for cytotoxicity. Biological results will then drive new synthetic targets to be modeled, and the loop will be repeated. This aim is innovative in that a multi-PI proposal involving the work of 3 labs at 2 different primarily undergraduate institutions (PUIs) will bring together different areas of expertise to tubulin inhibitor design. Furthermore, many of these approaches and methods are particularly innovative at a PUI. Third, we will apply and develop modular synthetic methods that give access to designed anti-tubulin heterocycles through two parallel synthetic strategies by: (1) applying and extending our published work while (2) investigating innovative strategies that employ C-H activation, thus significantly improving resource efficiency and potentially extending the substitution patterns available for analogue synthesis (including NH indole derivatives). Of note, all aims are independent as aim 2 can be performed with compounds made in aim 3 or by our previously published synthetic routes. Overall, we will perform basic research to improve anticancer agents while training the next generation of scientists.