{"title":"合成对结直肠癌有显著疗效的 LSD1/HDAC 抑制剂:体外和体内研究,包括患者生成的器官组织","authors":"Po-Yu Chou, Mei-Jung Lai, Kelvin K. Tsai, Li-Hsin Cheng, Yi-Wen Wu, Mei-Chuan Chen, Shiow-Lin Pan, Hsiu-O Ho, Kunal Nepali, Jing-Ping Liou","doi":"10.1021/acs.jmedchem.4c01098","DOIUrl":null,"url":null,"abstract":"Precedential evidence ascertaining the overexpression of LSD1 and HDACs in colorectal cancer spurred us to design a series of dual LSD1-HDAC inhibitors. Capitalizing on the modular nature of the three-component HDAC inhibitory model, tranylcypromine as a surface recognition motif was appended to zinc-binding motifs via diverse linkers. A compendium of hydroxamic acids was generated and evaluated for <i>in vitro</i> cytotoxicity against HCT-116 cells (human colorectal cancer cell lines). The most potent cell growth inhibitor <b>2</b> (GI<sub>50</sub> = 0.495 μMm HCT-116 cells) shows promising anticancer effects by reducing colony formation and inducing cell cycle arrest in HCT-116 cells. It exhibits preferential inhibition of HDAC6, along with potent inhibition of LSD1 compared to standard inhibitors. Moreover, Compound <b>2</b> upregulates acetyl-tubulin, acetyl-histone H3, and H3K4me2, indicative of LSD1 and HDAC inhibition. <i>In vivo</i>, it demonstrates significant antitumor activity against colorectal cancer, better than irinotecan, and effectively inhibits growth in patient-derived CRC organoids.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Syntheses of LSD1/HDAC Inhibitors with Demonstrated Efficacy against Colorectal Cancer: In Vitro and In Vivo Studies Including Patient-Derived Organoids\",\"authors\":\"Po-Yu Chou, Mei-Jung Lai, Kelvin K. Tsai, Li-Hsin Cheng, Yi-Wen Wu, Mei-Chuan Chen, Shiow-Lin Pan, Hsiu-O Ho, Kunal Nepali, Jing-Ping Liou\",\"doi\":\"10.1021/acs.jmedchem.4c01098\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Precedential evidence ascertaining the overexpression of LSD1 and HDACs in colorectal cancer spurred us to design a series of dual LSD1-HDAC inhibitors. Capitalizing on the modular nature of the three-component HDAC inhibitory model, tranylcypromine as a surface recognition motif was appended to zinc-binding motifs via diverse linkers. A compendium of hydroxamic acids was generated and evaluated for <i>in vitro</i> cytotoxicity against HCT-116 cells (human colorectal cancer cell lines). The most potent cell growth inhibitor <b>2</b> (GI<sub>50</sub> = 0.495 μMm HCT-116 cells) shows promising anticancer effects by reducing colony formation and inducing cell cycle arrest in HCT-116 cells. It exhibits preferential inhibition of HDAC6, along with potent inhibition of LSD1 compared to standard inhibitors. Moreover, Compound <b>2</b> upregulates acetyl-tubulin, acetyl-histone H3, and H3K4me2, indicative of LSD1 and HDAC inhibition. <i>In vivo</i>, it demonstrates significant antitumor activity against colorectal cancer, better than irinotecan, and effectively inhibits growth in patient-derived CRC organoids.\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-09-25\",\"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.4c01098\",\"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.4c01098","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Syntheses of LSD1/HDAC Inhibitors with Demonstrated Efficacy against Colorectal Cancer: In Vitro and In Vivo Studies Including Patient-Derived Organoids
Precedential evidence ascertaining the overexpression of LSD1 and HDACs in colorectal cancer spurred us to design a series of dual LSD1-HDAC inhibitors. Capitalizing on the modular nature of the three-component HDAC inhibitory model, tranylcypromine as a surface recognition motif was appended to zinc-binding motifs via diverse linkers. A compendium of hydroxamic acids was generated and evaluated for in vitro cytotoxicity against HCT-116 cells (human colorectal cancer cell lines). The most potent cell growth inhibitor 2 (GI50 = 0.495 μMm HCT-116 cells) shows promising anticancer effects by reducing colony formation and inducing cell cycle arrest in HCT-116 cells. It exhibits preferential inhibition of HDAC6, along with potent inhibition of LSD1 compared to standard inhibitors. Moreover, Compound 2 upregulates acetyl-tubulin, acetyl-histone H3, and H3K4me2, indicative of LSD1 and HDAC inhibition. In vivo, it demonstrates significant antitumor activity against colorectal cancer, better than irinotecan, and effectively inhibits growth in patient-derived CRC organoids.
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.