2. Academic Validation
  3. Marine-Derived Bromotyrosine Alkaloids as Potent hCYP1B1 Inhibitors to Overcome Paclitaxel Resistance

Marine-Derived Bromotyrosine Alkaloids as Potent hCYP1B1 Inhibitors to Overcome Paclitaxel Resistance

  • J Med Chem. 2026 Feb 12;69(3):3571-3587. doi: 10.1021/acs.jmedchem.5c03657.
Quan Xu 1 2,  Yuan Xiong 3,  Yanfen Fang 4,  Bei Zhao 3,  Biyu Yang 4,  Yu-Meng Hao 3,  Hong-Xia Dai 2,  Xiangyang Zhang 1,  Yi Chen 2 4,  Guang-Bo Ge 3,  Xu-Wen Li 2 4
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin 300072, China.
  • 2 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
  • 3 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine; Shanghai Frontiers Science Center of TCM Chemical Biology; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 4 State Key Laboratory of Chemical Biology, Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
PMID: 41614618 DOI: 10.1021/acs.jmedchem.5c03657
Abstract

Human Cytochrome P450 1B1 (hCYP1B1) overexpression is strongly associated with tumor drug resistance, making it an attractive target for overcoming chemotherapeutic resistance. Screening of a marine natural product library identified purpuramine D (10) as a potent hCYP1B1 inhibitor (IC50 = 11.89 nM). SAR-guided optimization led to a methylated oxime derivative 26a, which exhibited a nearly 10-fold improvement in activity (IC50 = 1.32 nM). Mechanistic studies revealed that 26a competitively binds to the hCYP1B1 catalytic pocket, supported by inhibition kinetics (Ki = 0.72 μM) and molecular dynamics simulations. In live cells, 26a inhibited hCYP1B1-mediated 17β-estradiol hydroxylation (IC50 = 2.21 μM) and reversed paclitaxel (PTX) resistance in both A549/PTX and H460/PTX cells (22.9-26.5-fold sensitization). In vivo, 26a synergized antitumor effects with PTX in an A549/PTX xenograft model (41.1% tumor growth inhibition) without evident toxicity. Collectively, 26a represents a novel marine-derived, metabolically stable hCYP1B1 inhibitor with high potential to reverse chemoresistance.

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