Multidrug resistance (MDR) has been shown to reduce the effectiveness of chemotherapy. Strategies to overcoming MDR have been widely explored in the last decades, leading to a generation of numerous small molecules targeting ABC and MRP transporters. Among the ABC family, ABCB1 plays key roles in the development of drug resistance and is the most well studied. In this work, we report the discovery of a non-toxic [1,2,4]triazolo[1,5-a]pyrimidin-7-one (WS-10) from our structurally diverse in-house compound collection that selectively modulates ABCB1-mediated multidrug resistance. WS-10 enhanced the intracellular accumulation of paclitaxel in SW620/Ad300 cells, but did not affect the expression of ABCB1 Protein and ABCB1 localization. The cellular thermal shift assay (CETSA) showed that WS-10 was able to bind to ABCB1, which could be responsible for the reversal effect of WS-10 toward paclitaxel and doxorubicin in SW620/Ad300 cells. Docking simulations were performed to show the possible binding modes of WS-10 within ABCB1 transporter. To conclude, WS-10 could be used as a template for designing new ABCB1 modulators to overcome ABCB1-mediated multidrug resistance.

已显示多药耐药性（MDR）会降低化疗的有效性。在过去的几十年中，人们广泛探索了克服MDR的策略，从而产生了许多针对ABC和MRP转运蛋白的小分子。在ABC家族中，ABCB1在耐药性的发展中起着关键作用，并且研究最深入。在这项工作中，我们报告了从我们结构多样的内部化合物集合中发现的一种无毒[1,2,4]三唑[1,5- a ]嘧啶-7-一（WS-10）的发现，该化合物选择性地调节ABCB1介导的多药耐药性。WS-10增强紫杉醇在SW620 / Ad300细胞中的细胞内积累，但不影响ABCB1蛋白的表达和ABCB1的定位。细胞热位移分析（CETSA）表明WS-10能够与ABCB1结合，这可能是WS-10在SW620 / Ad300细胞中对紫杉醇和阿霉素的逆转作用的原因。进行对接模拟以显示WS-10在ABCB1转运蛋白中的可能结合方式。总之，WS-10可以用作设计新的ABCB1调节剂的模板，以克服ABCB1介导的多药耐药性。