Zaman Shadid U, Pagare Piyusha P, Ma Hongguang, Hoyle Rosalie G, Zhang Yan, Li Jiong
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University Richmond Virginia 23298-0540 USA
Department of Oral and Craniofacial Molecular Biology, Virginia Commonwealth University Richmond Virginia 23298-0540 USA.
RSC Med Chem. 2024 Sep 13;15(11):3746-58. doi: 10.1039/d4md00122b.
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 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 suppressing oncogenic Wnt signaling.
已证明组蛋白去甲基化酶的KDM3家族（KDM3A和KDM3B）通过Wnt/β-连环蛋白信号通路在表观遗传上控制结直肠癌干细胞（CSCs）的功能特性。同时，一种广谱组蛋白去甲基化酶抑制剂IOX1主要通过抑制KDM3的酶活性来抑制Wnt诱导的结直肠癌发生。在这项工作中，设计并合成了几种具有不同连接子长度的cereblon（CRBN）招募型PROTAC，以IOX1作为弹头来靶向KDM3蛋白进行降解。合成的两种PROTAC对KDM3A和KDM3B表现出良好的降解特性和选择性。化合物4在肝酶方面表现出良好的代谢特性，且无hERG相关的心脏毒性。化合物4还显示出显著的抑制致癌Wnt信号传导的能力，以消除结直肠癌干细胞并抑制肿瘤生长，其效力比IOX1高约10至35倍。总之，本研究表明PROTAC为从IOX1骨架开发新型小分子提供了一种独特的分子工具，用于选择性降解KDM3以消除结直肠癌干细胞并抑制致癌Wnt信号传导。
