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

Targeting ABCB1 is a promising strategy in combating multidrug resistance. Our cell-based phenotypic screening led to the discovery of novel triazolo[1,5-<i>a</i>]pyrimidone-based ABCB1 modulators. Notably, <b>WS-917</b> 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, <b>WS-917</b> 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 <b>WS-917</b> holds promise for the development of more potent ABCB1 modulators.