Langston Steven P, Grossman Stephen, England Dylan, Afroze Roushan, Bence Neil, Bowman Douglas, Bump Nancy, Chau Ryan, Chuang Bei-Ching, Claiborne Christopher, Cohen Larry, Connolly Kelly, Duffey Matthew, Durvasula Nitya, Freeze Scott, Gallery Melissa, Galvin Katherine, Gaulin Jeffrey, Gershman Rachel, Greenspan Paul, Grieves Jessica, Guo Jianping, Gulavita Nanda, Hailu Shumet, He Xingyue, Hoar Kara, Hu Yongbo, Hu Zhigen, Ito Mitsuhiro, Kim Mi-Sook, Lane Scott Weston, Lok David, Lublinsky Anya, Mallender William, McIntyre Charles, Minissale James, Mizutani Hirotake, Mizutani Miho, Molchinova Nina, Ono Koji, Patil Ashok, Qian Mark, Riceberg Jessica, Shindi Vaishali, Sintchak Michael D, Song Keli, Soucy Teresa, Wang Yana, Xu He, Yang Xiaofeng, Zawadzka Agatha, Zhang Ji, Pulukuri Sai M
Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceuticals Company Ltd., Cambridge, Massachusetts 02139, United States.
Takeda Pharmaceuticals, Fujisawa, Kanagawa 251-0012, Japan.
J Med Chem. 2021 Mar 11;64(5):2501-2520. doi: 10.1021/acs.jmedchem.0c01491. Epub 2021 Feb 25.
SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO-TAK-981 adduct as the inhibitory species within the enzyme catalytic site. Optimization of selectivity against related enzymes as well as enhancement of mean residence time of the adduct were critical to the identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect and efficacy in preclinical tumor models, culminating in the identification of the clinical molecule TAK-981.
SUMO化是一种可逆的翻译后修饰，通过小泛素样修饰物（SUMO）蛋白的共价连接来调节蛋白质功能。蛋白质SUMO化过程涉及一个酶促级联反应，其第一步需要通过SUMO激活酶（SAE）催化的ATP依赖性过程来激活SUMO蛋白。在此，我们描述了TAK-981的鉴定，TAK-981是一种基于机制的SAE抑制剂，它在酶催化位点形成SUMO-TAK-981加合物作为抑制性物种。针对相关酶的选择性优化以及加合物平均驻留时间的延长对于鉴定具有有效细胞途径抑制作用的化合物至关重要，并最终在临床前肿瘤模型中产生延长的药效学效应和疗效，最终鉴定出临床分子TAK-981。
