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

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-<i>a</i>]pyrimidine derivative <b>WS-898</b> 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. <b>WS-898</b> 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 <b>WS-898</b> to ABCB1. Furthermore, <b>WS-898</b> stimulated the ATPase activity of ABCB1 but had minimal effects on cytochrome P450 3A4 (CYP3A4). Importantly, <b>WS-898</b> increased PTX sensitization <i>in vivo</i> without obvious toxicity. The results suggest that <b>WS-898</b> is a highly effective triazolo[1,5-<i>a</i>]pyrimidine-based ABCB1 inhibitor and shows promise in reversing ABCB1-mediated PTX resistance.