Structure-Based Design, Synthesis, and Biological Evaluation of New Triazolo[1,5-a]Pyrimidine Derivatives as Highly Potent and Orally Active ABCB1 Modulators
- 5 December 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (24), 15979-15996
- https://doi.org/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.Keywords
Funding Information
- China Postdoctoral Science Foundation (2018M630840, 2019M662518, 2019T120641)
- National Natural Science Foundation of China (31900875, 81703326, 81773562, 81973177)
- Program for Science & Technology Innovation Talents in Universities of Henan Province (21HASTIT045)
- 1000 Talents Program of Central plains (204200510023)
- Medical Science and Technique Foundation of Henan Province (2018020486, SB201901101)
- Science and Technique Foundation of Henan Province (202102310413)
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