Ubiquitination and degradation of SUMO1 by small-molecule degraders extends survival of mice with patient-derived tumors.
Ubiquitination and degradation of SUMO1 by small-molecule degraders extends survival of mice with patient-derived tumors.
复制标题
DOI：
10.1126/scitranslmed.abh1486
复制
发表时间：
2021-10-13
影响因子：
17.1
通讯作者：
Hao, Chunhai
中科院分区：
文献类型：
--
作者：
Bellail, Anita C.;Jin, Hong Ri;Lo, Ho-Yin;Jung, Sung Han;Hamdouchi, Chafiq;Kim, Daeho;Higgins, Ryan K.;Blanck, Maximilian;le Sage, Carlos;Cross, Benedict C. S.;Li, Jing;Mosley, Amber L.;Wijeratne, Aruna B.;Jiang, Wen;Ghosh, Manali;Zhao, Yin Quan;Hauck, Paula M.;Shekhar, Anantha;Hao, Chunhai
发现小分子降解剂激活泛素连接酶介导的泛素化和癌细胞中靶向癌蛋白的降解一直是一个难以捉摸的治疗策略。在这里，我们报告了一个基于癌细胞的药物筛选的NCI药物样化合物库，使小泛素相关的修饰剂1（SUMO 1）的小分子降解剂的鉴定。命中化合物CPD 1的类似物的结构-活性关系研究导致鉴定出在体外和体内具有改进的性质和抗癌效力的先导化合物HB 007。基因组规模的CRISPR-Cas9敲除筛选鉴定了HB 007活性所需的cullin 1（CUL 1）E3泛素连接酶的底物受体F-box蛋白42（FBXO 42）。使用HB 007下拉蛋白质组学分析，我们确定HB 007的结合蛋白为细胞质活化/增殖相关蛋白1（CAPRIN 1）。生物层干涉法和复合竞争性免疫印迹测定证实了HB 007与CAPRIN 1结合的选择性。当与CAPRIN 1结合时，HB 007诱导CAPRIN 1与FBXO 42的相互作用。然后FBXO 42将SUMO 1募集到CAPRIN 1-CUL 1-FBXO 42泛素连接酶复合物中，其中SUMO 1在几种人类癌细胞中被泛素化。HB 007选择性降解植入小鼠的患者肿瘤来源异种移植物中的SUMO 1。全身给予HB 007可抑制小鼠中患者来源的脑癌、乳腺癌、结肠癌和肺癌的进展，并增加动物的存活率。这种基于癌细胞的筛选方法能够发现SUMO 1的小分子降解物，并可能用于鉴定癌蛋白的其他小分子降解物。
Discovery of small-molecule degraders that activate ubiquitin ligase–mediated ubiquitination and degradation of targeted oncoproteins in cancer cells has been an elusive therapeutic strategy. Here, we report a cancer cell–based drug screen of the NCI drug-like compounds library that enabled identification of small-molecule degraders of the small ubiquitin-related modifier 1 (SUMO1). Structure-activity relationship studies of analogs of the hit compound CPD1 led to identification of a lead compound HB007 with improved properties and anticancer potency in vitro and in vivo. A genome-scale CRISPR-Cas9 knockout screen identified the substrate receptor F-box protein 42 (FBXO42) of cullin 1 (CUL1) E3 ubiquitin ligase as required for HB007 activity. Using HB007 pull-down proteomics assays, we pinpointed HB007’s binding protein as the cytoplasmic activation/proliferation-associated protein 1 (CAPRIN1). Biolayer interferometry and compound competitive immunoblot assays confirmed the selectivity of HB007’s binding to CAPRIN1. When bound to CAPRIN1, HB007 induced the interaction of CAPRIN1 with FBXO42. FBXO42 then recruited SUMO1 to the CAPRIN1-CUL1-FBXO42 ubiquitin ligase complex, where SUMO1 was ubiquitinated in several of human cancer cells. HB007 selectively degraded SUMO1 in patient tumor–derived xenografts implanted into mice. Systemic administration of HB007 inhibited the progression of patient-derived brain, breast, colon, and lung cancers in mice and increased survival of the animals. This cancer cell–based screening approach enabled discovery of a small-molecule degrader of SUMO1 and may be useful for identifying other small-molecule degraders of oncoproteins.
登录
查看更多内容
影响因子：
11.8
作者：
Cubenas-Potts, Caelin;Matunis, Michael J.
通讯作者：
Matunis, Michael J.
影响因子：
2.3
作者：
Bloom J;Peschiaroli A;Demartino G;Pagano M
通讯作者：
Pagano M
影响因子：
16.6
作者：
Bellail, Anita C.;Olson, Jeffrey J.;Hao, Chunhai
通讯作者：
Hao, Chunhai
影响因子：
21.3
作者：
Kim, Jung Hwa;Choi, Hee June;Baek, Sung Hee
通讯作者：
Baek, Sung Hee
影响因子：
4
作者：
Evdokimov, Evgenij;Sharma, Prashant;Kuehn, Michael R.
通讯作者：
Kuehn, Michael R.