Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 21, Pages 16187-16204Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01498
Keywords
-
Categories
Funding
- National Natural Science Foundation of China [81773562, 81973177]
- Program for Science and Technology Innovation Talents in Universities of Henan Province [21HASTIT045]
- Medical Science and Technique Foundation of Henan Province [2018020486, SB201901101]
- Science and Technique Foundation of Henan Province [202102310413]
- 1000 Talents Program of Central plains [204200510023]
- Natural Science Foundation of Henan Province [212300410270]
Ask authors/readers for more resources
The triazolo[1,5-a]pyrimidine derivative WS-898 was discovered as a highly effective ABCB1 inhibitor capable of reversing PTX resistance in cells. WS-898 inhibited the efflux function of ABCB1, leading to increased intracellular PTX concentration and enhanced drug efficacy. Additionally, WS-898 showed promising results in in vivo PTX sensitization without causing obvious toxicity.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available