Discovery of TAK-981, a First-in-Class Inhibitor of SUMO-Activating Enzyme for the Treatment of Cancer
Discovery of TAK-981, a First-in-Class Inhibitor of SUMO-Activating Enzyme for the Treatment of Cancer
复制标题
DOI：
10.1021/acs.jmedchem.0c01491
复制
发表时间：
2021-02-25
影响因子：
7.3
通讯作者：
Pulukuri, Sai M.
中科院分区：
文献类型：
--
作者：
Langston, Steven P.;Grossman, Stephen;Pulukuri, Sai M.
SUMO 化是一种可逆的翻译后修饰，通过共价连接小型泛素样修饰剂 (SUMO) 蛋白来调节蛋白质功能。 SUMO 化蛋白质的过程涉及酶级联，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 蛋白质。在这里，我们描述了 TAK-981 的鉴定，TAK-981 是一种基于机制的 SAE 抑制剂，它形成 SUMO-TAK-981 加合物作为酶催化位点内的抑制物质。优化针对相关酶的选择性以及延长加合物的平均停留时间对于鉴定具有有效细胞途径抑制作用的化合物以及最终在临床前肿瘤模型中延长药效作用和功效至关重要，最终鉴定出临床分子 TAK-981。
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.