2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2023 Nov 5;259:115668. doi: 10.1016/j.ejmech.2023.115668.
Yuntao Ma 1,  Fernando Josa-Prado 2,  Jacob Nathaniel Essif 3,  Shuqi Liu 4,  Shuo Li 1,  Daniel Lucena-Agell 2,  Peter Yw Chan 3,  Kenneth Goossens 2,  Rafael Hortigüela 2,  Ruth Matesanz 2,  Yingjie Wang 4,  Federico Gago 5,  Hongbo Wang 4,  April Risinger 3,  J Fernando Diaz 6,  Wei-Shuo Fang 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Ministry of Health Key Laboratory of Biosynthesis of Natural Products, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 2A Nan Wei Road, Beijing, 100050, China.
  • 2 Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, Madrid, 28040, Spain.
  • 3 Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, United States.
  • 4 Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China.
  • 5 Área de Farmacología, Departamento de Ciencias Biomédicas, Unidad Asociada al Instituto de Química Médica del CSIC, Universidad de Alcalá, E-28805, Alcalá de Henares, Madrid, Spain.
  • 6 Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, Madrid, 28040, Spain. Electronic address: fer@cib.csic.es.
  • 7 State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Ministry of Health Key Laboratory of Biosynthesis of Natural Products, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 2A Nan Wei Road, Beijing, 100050, China. Electronic address: wfang@imm.ac.cn.
PMID: 37490800 DOI: 10.1016/j.ejmech.2023.115668
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.

Keywords

Curved conformation; Microtubule; Persistent cytotoxicity; Straight conformation; Taxane; Tubulin.

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