{"title":"基于细胞的筛选发现了一种用于治疗多药耐药性的强效口服 ABCB1 调节剂","authors":"Shuai Wang, Sai-Qi Wang, Xiao-Bing Chen, Qian Xu, Hao Deng, Qiu-Xu Teng, Zhe-Sheng Chen, Xuyao Zhang, Fen-Er Chen","doi":"10.1021/acs.jmedchem.4c01081","DOIUrl":null,"url":null,"abstract":"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 (IC<sub>50</sub> = 5 nM). Mechanistic elucidation revealed that this compound substantially augmented intracellular paclitaxel and [<sup>3</sup>H]-paclitaxel, concurrently mitigating the efflux of [<sup>3</sup>H]-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.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Cell-Based Screen Identifies a Highly Potent and Orally Available ABCB1 Modulator for Treatment of Multidrug Resistance\",\"authors\":\"Shuai Wang, Sai-Qi Wang, Xiao-Bing Chen, Qian Xu, Hao Deng, Qiu-Xu Teng, Zhe-Sheng Chen, Xuyao Zhang, Fen-Er Chen\",\"doi\":\"10.1021/acs.jmedchem.4c01081\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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 (IC<sub>50</sub> = 5 nM). Mechanistic elucidation revealed that this compound substantially augmented intracellular paclitaxel and [<sup>3</sup>H]-paclitaxel, concurrently mitigating the efflux of [<sup>3</sup>H]-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.\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-10-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jmedchem.4c01081\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c01081","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
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.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.