Abstract 3841: Biologic evaluation of heterocyclic pyrimidines as novel tubulin inhibitors targeting the colchicine binding site

Abstract

Abstract Interfering with tubulin dynamics is an attractive strategy for cancer therapy, and tubulin-targeting agents are some of the most widely used chemotherapeutic drugs. Current FDA-approved tubulin inhibitors target either the taxane site (e.g., paclitaxel) or the vinca alkaloid site (e.g., vinblastine). However, their clinical efficacy is often limited by the development of multidrug resistance and a narrow therapeutic index. Tubulin inhibitors interacting with the colchicine site have shown potent anticancer activities, are generally less susceptible to multidrug resistance, and can disrupt tumor vasculature, leading to rapid tumor cell apoptosis. Here, we report on the biologic evaluation of heterocyclic pyrimidines as a new class of tubulin inhibitors targeting the colchicine binding site with a significantly improved therapeutic index. One of the most promising compounds of the series, SB157, was able to strongly inhibit tubulin polymerization and induce cytotoxicity in cancer cells in vitro. We have also obtained the high-resolution X-ray crystal structure for SB157, confirming its direct binding to the colchicine binding site in tubulin, and elucidated the detailed molecular interactions. SB157 significantly inhibited tumor growth in an A375 melanoma xenograft model, and the tumors revealed elevated apoptotic activity and extensive disruption of tumor vasculature. Finally, we demonstrated that SB157 significantly overcame clinically relevant multidrug resistance in a paclitaxel-resistant PC-3/TxR prostate cancer xenograft mouse model. Collectively, these studies provide preclinical proof of concept and structural basis to support the continued development of SB157 and optimization of this scaffold as an improved class of tubulin inhibitors for cancer therapy. Citation Format: Kinsie Arnst. Biologic evaluation of heterocyclic pyrimidines as novel tubulin inhibitors targeting the colchicine binding site [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3841.