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

IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Shadid U. Zaman, Piyusha P. Pagare, Hongguang Ma, Rosalie G. Hoyle, Yan Zhang and Jiong Li
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引用次数: 0

摘要

研究表明,组蛋白去甲基化酶 KDM3 家族(KDM3A 和 KDM3B)通过 Wnt/β-catenin 信号转导,从表观遗传学角度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 诱导的结直肠肿瘤发生。本研究以 IOX1 为弹头,设计并合成了几种具有不同连接长度的脑龙(CRBN)募集 PROTACs,以靶向降解 KDM3 蛋白。合成的 PROTACs 中有两种对 KDM3A 和 KDM3B 具有良好的降解特性和选择性。化合物 4 在体外肝酶代谢方面表现良好,并且没有与 hERG 相关的心脏毒性。化合物 4 在抑制致癌 Wnt 信号转导以消除结直肠癌 CSCs 和抑制肿瘤生长方面也表现出惊人的能力,其效力比 IOX1 提高了约 10 至 35 倍。总之,这项研究表明,PROTACs 为从 IOX1 骨架中开发新型小分子提供了一种独特的分子工具,可选择性地降解 KDM3,从而通过抑制致癌 Wnt 信号消除结直肠癌 CSCs。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Novel PROTAC probes targeting KDM3 degradation to eliminate colorectal cancer stem cells through inhibition of Wnt/β-catenin signaling†

Novel PROTAC probes targeting KDM3 degradation to eliminate colorectal cancer stem cells through inhibition of Wnt/β-catenin signaling†

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.

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CiteScore
5.80
自引率
2.40%
发文量
129
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