2. Academic Validation
  3. Cell-Based Screen Identifies a Highly Potent and Orally Available ABCB1 Modulator for Treatment of Multidrug Resistance

Cell-Based Screen Identifies a Highly Potent and Orally Available ABCB1 Modulator for Treatment of Multidrug Resistance

  • J Med Chem. 2024 Oct 19. doi: 10.1021/acs.jmedchem.4c01081.
Shuai Wang 1 2 3,  Sai-Qi Wang 4,  Xiao-Bing Chen 4,  Qian Xu 1 3,  Hao Deng 1 3,  Qiu-Xu Teng 5,  Zhe-Sheng Chen 5,  Xuyao Zhang 6,  Fen-Er Chen 1 2 3 7
Affiliations

Affiliations

  • 1 Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.
  • 2 Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, College of Pharmacy, Yanji, Jilin 133002, China.
  • 3 Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China.
  • 4 Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
  • 5 College of Pharmacy and Health Sciences, St. John's University, Queens, New York 11439, United States.
  • 6 Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 7 School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China.
PMID: 39425773 DOI: 10.1021/acs.jmedchem.4c01081
Abstract

Targeting ABCB1 is a promising strategy in combating multidrug resistance. Our cell-based phenotypic screening led to the discovery of novel triazolo[1,5-a]pyrimidone-based ABCB1 modulators. Notably, WS-917 was identified as a significant contributor to heightened sensitization of human colorectal adenocarcinoma cells (SW620/Ad300) to paclitaxel (IC50 = 5 nM). Mechanistic elucidation revealed that this compound substantially augmented intracellular paclitaxel and [3H]-paclitaxel, concurrently mitigating the efflux of [3H]-paclitaxel in SW620/Ad300 through the inhibition of ABCB1 efflux. The cellular thermal shift assay underscored its ability to stabilize ABCB1 through direct binding. Additionally, WS-917 induced stimulation of ABCB1 ATPase activity while exhibiting negligible inhibitory effect against CYP3A4. Remarkable was its capacity to enhance the sensitivity of SW620/Ad300 to paclitaxel, as well as the sensitivity of CT26/TAXOL to paclitaxel and PD-L1 inhibitor (Atezolizumab) in vivo, all achieved without inducing observable toxicity. The discovery of WS-917 holds promise for the development of more potent ABCB1 modulators.

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