Structure-based discovery of potent USP28 inhibitors derived from Vismodegib
Structure-based discovery of potent USP28 inhibitors derived from Vismodegib
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DOI：
10.1016/j.ejmech.2023.115369
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发表时间：
2023-04-17
影响因子：
6.7
通讯作者：
Xiong，Bing
中科院分区：
文献类型：
--
作者：
Zhou，Di;Xu，Zhuo;Xiong，Bing
泛素特异性蛋白酶（USP）28在多种类型的癌症中过表达。有效的USP 28抑制剂的开发仍处于初级阶段。我们先前报道了通过筛选市售药物库发现Vismodegib作为USP 28抑制剂。在本文中，我们报告了我们首次解决与USP 28结合的Vismodegib的共晶结构的努力，以及随后基于结构的优化，导致一系列Vismodegib衍生物作为有效的USP 28抑制剂。基于共晶结构，进行了详细的SAR探索，以提供比Vismodegib更有效的USP 28抑制剂。在USP 28上具有高效价的代表性化合物9 l、9 o和9 p显示出对USP 2、USP 7、USP 8、USP 9 x、UCHL 3和UCHL 5的高选择性。详细的细胞实验表明化合物9 l、9 o和9 p对人结直肠癌和肺鳞癌细胞均具有细胞毒性，并显著增强结直肠癌细胞对瑞格非尼的敏感性。进一步的免疫印迹分析表明，化合物9 l、9 o和9 p可剂量依赖性地通过泛素-蛋白酶体系统下调c-Myc的表达，其抗肿瘤作用可能主要是通过抑制USP 28而非Hedgehog-Smoothened途径实现的。因此，我们的工作提供了一系列新的和有效的USP 28抑制剂来自维莫德吉，并可能有助于开发USP 28抑制剂。
Ubiquitin-specific proteases (USPs) 28 is overexpressed in multiple types of cancers. The development of potent USP28 inhibitors is still in primitive stage. We previously reported our discovery of Vismodegib as a USP28 inhibitor by screening a commercially available drug library. Herein, we report our efforts to solve the cocrystal structure of Vismodegib bound to USP28 for the first time and subsequent structure-based optimization leading to a series of Vismodegib derivatives as potent USP28 inhibitors. Based on the cocrystal structure, elaborative SARs exploration was carried out to afford much more potent USP28 inhibitors than Vismodegib. The representative compounds9l,9oand9pbearing high potency on USP28 showed high selectivity over USP2, USP7, USP8, USP9x, UCHL3 and UCHL5. The detailed cellular assay suggested that compounds9l,9oand9pcould cause cytotoxicity in both human colorectal cancer and lung squamous carcinoma cells and significantly enhance the sensitivity of colorectal cancer cells to Regorafenib. Further immunoblotting analysis indicated that compounds9l,9oand9pcould dose-dependently down-regulate the cellular level of c-Myc through ubiquitin-proteasome system and anti-cancer effects could mainly be attributed to their inhibition on USP28 but not involving the Hedgehog-Smoothened pathway. Thus, our work provided a series of novel and potent USP28 inhibitors derived from Vismodegib and may contribute to the development of USP28 inhibitors.