Modulation of taxane binding to tubulin curved and straight conformations by systematic 3′N modification provides for improved microtubule binding, persistent cytotoxicity and in vivo potency

Yuntao Ma, Fernando Josa-Prado, Jacob Nathaniel Essif, Shuqi Liu, Shuo Li, Daniel Lucena-Agell, Peter YW Chan, Kenneth Goossens, Rafael Hortigüela, Ruth Matesanz, Yingjie Wang, Federico Gago, Hongbo Wang, April Risinger, J. Fernando Diaz, Wei Shuo Fang

Research output: Contribution to journalArticlepeer-review

Abstract

The taxane class of microtubule stabilizers are some of the most effective and widely used chemotherapeutics. The anticancer activity of taxanes arises from their ability to induce tubulin assembly by selectively recognizing the curved (c-) conformation in unassembled tubulin as compared to the straight (s-) conformation in assembled tubulin. We first designed and synthesized a series of 3′N-modified taxanes bearing covalent groups. Instead of discovering covalent taxanes, we found a series of non-covalent taxanes 2, in which the 3′N side chain was found to be essential for cytotoxicity due to its role in locking tubulin in the s-conformation. A representative compound bearing an acrylamide moiety (2h) exhibited increased binding affinity to the unassembled tubulin c-conformation and less cytotoxicity than paclitaxel. Further exploration of chemical space around 2h afforded a new series 3, in which derivatives such as 3l bind more tightly to both the s- and c-conformations of tubulin compared to paclitaxel, leading to more efficient promotion of tubulin polymerization and a greater persistence of in vitro efficacy against breast cancer cells after drug washout. Although 3l also had improved in vivo potency as compared to paclitaxel, it was also associated with increased systemic toxicity that required localized, intratumoral injection to observe potent and prolonged antitumor efficacy.

Original languageEnglish (US)
Article number115668
JournalEuropean Journal of Medicinal Chemistry
Volume259
DOIs
StatePublished - Nov 5 2023

Keywords

  • Curved conformation
  • Microtubule
  • Persistent cytotoxicity
  • Straight conformation
  • Taxane
  • Tubulin

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Organic Chemistry

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