Structure-Based Design, Synthesis, and Biological Evaluation of New Triazolo[1,5-a]Pyrimidine Derivatives as Highly Potent and Orally Active ABCB1 Modulators
| Autor: | Xiao-Bing Chen, Sai-Qi Wang, Mengru Wang, Zi-Ning Lei, Hong-Min Liu, Xiao-Han Yuan, Linlin Yang, Shuai Wang, Bin Yu, Jun-Feng Huo, Qiu-Xu Teng, Zhe-Sheng Chen |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Thermal shift assay Pyrimidine Chemistry Cell growth Pharmacology 01 natural sciences 0104 chemical sciences Multiple drug resistance 010404 medicinal & biomolecular chemistry 03 medical and health sciences chemistry.chemical_compound In vivo Drug Discovery Molecular Medicine Efflux IC50 Intracellular 030304 developmental biology |
| Zdroj: | Journal of Medicinal Chemistry. 63:15979-15996 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c01741 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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