Discovery of the Triazolo[1,5- a]Pyrimidine-Based Derivative WS-898 as a Highly Efficacious and Orally Bioavailable ABCB1 Inhibitor Capable of Overcoming Multidrug Resistance

  • J Med Chem. 2021 Nov 11;64(21):16187-16204. doi: 10.1021/acs.jmedchem.1c01498.
Shuai Wang  1 ,  Sai-Qi Wang  2 ,  Qiu-Xu Teng  3 ,  Zi-Ning Lei  3 ,  Zhe-Sheng Chen  3 ,  Xiao-Bing Chen  2 ,  Hong-Min Liu  1 ,  Bin Yu  1
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.
PMID: 34723530 DOI: 10.1021/acs.jmedchem.1c01498
Abstract

Targeting P-glycoprotein (ABCB1 or P-gp) has been recognized as a promising strategy to overcome multidrug resistance. Here, we reported our medicinal chemistry efforts that led to the discovery of the triazolo[1,5-a]pyrimidine derivative WS-898 as a highly effective ABCB1 inhibitor capable of reversing paclitaxel (PTX) resistance in drug-resistant SW620/Ad300, KB-C2, and HEK293/ABCB1 cells (IC50 = 5.0, 3.67, and 3.68 nM, respectively), more potent than verapamil and zosuquidar. WS-898 inhibited the efflux function of ABCB1, thus leading to decreased efflux and increased intracellular PTX concentration in SW620/Ad300 cells. The cellular thermal shift assay indicated direct engagement of WS-898 to ABCB1. Furthermore, WS-898 stimulated the ATPase activity of ABCB1 but had minimal effects on Cytochrome P450 3A4 (CYP3A4). Importantly, WS-898 increased PTX sensitization in vivo without obvious toxicity. The results suggest that WS-898 is a highly effective triazolo[1,5-a]pyrimidine-based ABCB1 inhibitor and shows promise in reversing ABCB1-mediated PTX resistance.

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