Shadid U. Zaman, Piyusha P. Pagare, Hongguang Ma, Rosalie G. Hoyle, Yan Zhang and Jiong Li
{"title":"以 KDM3 降解为靶点的新型 PROTAC 探针通过抑制 Wnt/β-catenin 信号转导消除结直肠癌干细胞","authors":"Shadid U. Zaman, Piyusha P. Pagare, Hongguang Ma, Rosalie G. Hoyle, Yan Zhang and Jiong Li","doi":"10.1039/D4MD00122B","DOIUrl":null,"url":null,"abstract":"<p >It has been demonstrated that the KDM3 family of histone demethylases (KDM3A and KDM3B) epigenetically control the functional properties of colorectal cancer stem cells (CSCs) through Wnt/β-catenin signaling. Meanwhile, a broad-spectrum histone demethylase inhibitor, IOX1, suppresses Wnt-induced colorectal tumorigenesis predominantly through inhibiting the enzymatic activity of KDM3. In this work, several cereblon (CRBN)-recruiting PROTACs with various linker lengths were designed and synthesized using IOX1 as a warhead to target KDM3 proteins for degradation. Two of the synthesized PROTACs demonstrated favorable degradation profile and selectivity towards KDM3A and KDM3B. Compound <strong>4</strong> demonstrated favorable <em>in vitro</em> metabolic profile in liver enzymes as well as no hERG-associated cardiotoxicity. Compound <strong>4</strong> also showed dramatic ability in suppressing oncogenic Wnt signaling to eliminate colorectal CSCs and inhibit tumor growth, with around 10- to 35-fold increased potency over IOX1. In summary, this study suggests that PROTACs provide a unique molecular tool for the development of novel small molecules from the IOX1 skeleton for selective degradation of KDM3 to eliminate colorectal CSCs <em>via</em> suppressing oncogenic Wnt signaling.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 11","pages":" 3746-3758"},"PeriodicalIF":4.1000,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00122b?page=search","citationCount":"0","resultStr":"{\"title\":\"Novel PROTAC probes targeting KDM3 degradation to eliminate colorectal cancer stem cells through inhibition of Wnt/β-catenin signaling†\",\"authors\":\"Shadid U. Zaman, Piyusha P. Pagare, Hongguang Ma, Rosalie G. Hoyle, Yan Zhang and Jiong Li\",\"doi\":\"10.1039/D4MD00122B\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >It has been demonstrated that the KDM3 family of histone demethylases (KDM3A and KDM3B) epigenetically control the functional properties of colorectal cancer stem cells (CSCs) through Wnt/β-catenin signaling. Meanwhile, a broad-spectrum histone demethylase inhibitor, IOX1, suppresses Wnt-induced colorectal tumorigenesis predominantly through inhibiting the enzymatic activity of KDM3. In this work, several cereblon (CRBN)-recruiting PROTACs with various linker lengths were designed and synthesized using IOX1 as a warhead to target KDM3 proteins for degradation. Two of the synthesized PROTACs demonstrated favorable degradation profile and selectivity towards KDM3A and KDM3B. Compound <strong>4</strong> demonstrated favorable <em>in vitro</em> metabolic profile in liver enzymes as well as no hERG-associated cardiotoxicity. Compound <strong>4</strong> also showed dramatic ability in suppressing oncogenic Wnt signaling to eliminate colorectal CSCs and inhibit tumor growth, with around 10- to 35-fold increased potency over IOX1. In summary, this study suggests that PROTACs provide a unique molecular tool for the development of novel small molecules from the IOX1 skeleton for selective degradation of KDM3 to eliminate colorectal CSCs <em>via</em> suppressing oncogenic Wnt signaling.</p>\",\"PeriodicalId\":21462,\"journal\":{\"name\":\"RSC medicinal chemistry\",\"volume\":\" 11\",\"pages\":\" 3746-3758\"},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-09-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00122b?page=search\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"RSC medicinal chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.rsc.org/en/content/articlelanding/2024/md/d4md00122b\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"RSC medicinal chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.rsc.org/en/content/articlelanding/2024/md/d4md00122b","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Novel PROTAC probes targeting KDM3 degradation to eliminate colorectal cancer stem cells through inhibition of Wnt/β-catenin signaling†
It has been demonstrated that the KDM3 family of histone demethylases (KDM3A and KDM3B) epigenetically control the functional properties of colorectal cancer stem cells (CSCs) through Wnt/β-catenin signaling. Meanwhile, a broad-spectrum histone demethylase inhibitor, IOX1, suppresses Wnt-induced colorectal tumorigenesis predominantly through inhibiting the enzymatic activity of KDM3. In this work, several cereblon (CRBN)-recruiting PROTACs with various linker lengths were designed and synthesized using IOX1 as a warhead to target KDM3 proteins for degradation. Two of the synthesized PROTACs demonstrated favorable degradation profile and selectivity towards KDM3A and KDM3B. Compound 4 demonstrated favorable in vitro metabolic profile in liver enzymes as well as no hERG-associated cardiotoxicity. Compound 4 also showed dramatic ability in suppressing oncogenic Wnt signaling to eliminate colorectal CSCs and inhibit tumor growth, with around 10- to 35-fold increased potency over IOX1. In summary, this study suggests that PROTACs provide a unique molecular tool for the development of novel small molecules from the IOX1 skeleton for selective degradation of KDM3 to eliminate colorectal CSCs via suppressing oncogenic Wnt signaling.