Abstract 3214: C-seco taxanes with 7, 9-linkages exhibit better activity in drug-resistant tumor cells

Abstract

Abstract Taxanes are a group of very successful MT stabilizing agents in cancer chemotherapy, although they suffer from tumor drug resistance, which compromises clinical efficacy. Many efforts were made in our labs to the structural modification of paclitaxel to improve efficacy against tumor drug resistance mediated by multiple mechanisms, with the emphasis on two clinically relevant ones: P-glycoprotein (Pgp) and β-III tubulin overexpression. While Pgp mediated multidrug resistance has been extensively explored and applied to the drug discovery projects, β-III tubulin overexpression related drug resistance was much less explored. The β-III tubulin isotype was found to play an important role in conferring resistance to MT stabilizing agents only in recent decade. It has also been identified as a survival factor in several types of cancers, thus conferring resistance to various anticancer agents, such as MT destabilizing agents and DNA interacting agents. We have found some high affinity taxanes (e.g. LX2-32C, Yg-3-46a) exhibited their activity toward Pgp efflux pump and also β-III tubulin mediated drug resistance. However, they did not show greater specificity for the β-III tubulin isotype. Based on a C-seco taxane IDN5390 which was reported to be more selectively interacted with β-III tubulin than paclitaxel, we have succeeded in the design and synthesis of 7,9-O-linked C-seco taxanes with different linkages. Some of them exhibited better activity than IDN5390, and the activities were found sensitive to the structural changes of the linkers. Citation Format: Yong Tang, Pei Cai, Javier Rodríguez-Salarisch, J. Fernando Díaz, Weishuo Fang. C-seco taxanes with 7, 9-linkages exhibit better activity in drug-resistant tumor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3214. doi:10.1158/1538-7445.AM2014-3214