2. Academic Validation
  3. Structure-Based Design, Synthesis, and Biological Evaluation of New Triazolo[1,5- a]Pyrimidine Derivatives as Highly Potent and Orally Active ABCB1 Modulators

Structure-Based Design, Synthesis, and Biological Evaluation of New Triazolo[1,5- a]Pyrimidine Derivatives as Highly Potent and Orally Active ABCB1 Modulators

  • J Med Chem. 2020 Dec 24;63(24):15979-15996. doi: 10.1021/acs.jmedchem.0c01741.
Shuai Wang 1,  Sai-Qi Wang 2,  Qiu-Xu Teng 3,  Linlin Yang 4,  Zi-Ning Lei 3,  Xiao-Han Yuan 1,  Jun-Feng Huo 1,  Xiao-Bing Chen 2,  Mengru Wang 4,  Bin Yu 1,  Zhe-Sheng Chen 3,  Hong-Min Liu 1
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China.
  • 2 Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Henan Cancer Institute, Zhengzhou 450008, China.
  • 3 College of Pharmacy and Health Sciences, St. John's University, Queens, New York 11439, United States.
  • 4 Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
PMID: 33280384 DOI: 10.1021/acs.jmedchem.0c01741
Abstract

ABCB1 is a promising therapeutic target for overcoming multidrug resistance (MDR). In this work, we reported the structure-based design of triazolo[1,5-a]pyrimidines as new ABCB1 modulators, of which WS-691 significantly increased sensitization of ABCB1-overexpressed SW620/Ad300 cells to paclitaxel (PTX) (IC50 = 22.02 nM). Mechanistic studies indicated that WS-691 significantly increased the intracellular concentration of PTX and [3H]-PTX while decreasing the efflux of [3H]-PTX in SW620/Ad300 cells by inhibiting the efflux function of ABCB1. The cellular thermal shift assay suggested that WS-691 could stabilize ABCB1 by directly binding to ABCB1. WS-691 could stimulate the activity of ABCB1 ATPase but had almost no inhibitory activity against CYP3A4. Importantly, WS-691 increased the sensitivity of SW620/Ad300 cells to PTX in vivo without observed toxicity. Collectively, WS-691 is a highly potent and orally active ABCB1 modulator capable of overcoming MDR. The triazolo[1,5-a]pyrimidine may be a promising scaffold for developing more potent ABCB1 modulators.

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