Enhancing the Scalability and Therapeutic Window of Taccalonolide-based Chemotherapeutics for the Treatment of Triple-negative Breast Cancers

Abstract ID 95310 Poster Board 247 Triple-Negative Breast Cancers (TNBCs) lack targeted treatment options and are effectively treated with chemotherapeutic regimens that often include microtubule stabilizing drugs such as paclitaxel and docetaxel. These drugs work by electrostatically binding and inhibiting depolymerization of microtubules resulting in mitotic arrest and apoptosis of cancer cells. While clinically effective, these drugs are vulnerable to chemoresistance, especially via transporter-mediated drug efflux. We have identified a novel class of plant-derived microtubule stabilizers called taccalonolides (taccas) that can covalently bind and irreversibly stabilize the microtubule cytoskeleton thus limiting the ability of transporters to capture and remove free drug. Despite their ability to retain efficacy in taxane-resistant tumors, the taccalonolides possess several limitations that currently preclude clinical development, including a short serum half-life and narrow therapeutic window. We performed in vivo PET/CT imaging with 18FTaccalonolide AF (TAF) which demonstrated rapid and persistent accumulation of the radiolabeled compound in the gallbladder and small intestine. Follow-up Pharmacokinetic (PK) studies confirmed rapid accumulation of TAF in the gall bladder. We hypothesize that modifications that increase the serum binding of the taccalonolides or incorporate them as payloads in antibody-drug conjugates could improve the bioavailability and therapeutic window of this drug class. Another major limitation to the clinical development of taccalonolides is that they are not synthetically tractable and can only be obtained by semi-synthesis of a rare natural product. The crystal structure of the taccalonolide-microtubule complex along with cellular binding studies have defined the taccalonolide pharmacophore and provided the opportunity to synthesize simplified taccalonolide analogs (taccalogs). We have taken a fragment-based approach to identify taccalonolide-inspired small molecules that interact with tubulin and promote cytotoxicity to TNBC cells. Our initial efforts have identified taccalogs with potency as low as 46 nM in TNBC cell lines that have greater cytotoxic efficacy than paclitaxel and directly interact with tubulin in biochemical assays. However, these simplified compounds lack the specificity of the natural product and second-generation compounds are being developed to improve target specificity. Together, these findings offer critical insights into an understanding of the natural taccalonolides and inform the development of synthetic taccalogs with the ultimate goal of identifying an optimal lead compound for the treatment of drug-resistant TNBC.