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-a]pyrimidone-based ABCB1 modulators.
Notably, WS-917 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, WS-917 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 WS-917 holds promise for the development
of more potent ABCB1 modulators.