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Discovery of TAK-981, a First-in-Class Inhibitor of SUMO-Activating Enzyme for the Treatment of Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-02-25 , DOI: 10.1021/acs.jmedchem.0c01491
Steven P. Langston 1 , Stephen Grossman 1 , Dylan England 1 , Roushan Afroze 1 , Neil Bence 1 , Douglas Bowman 1 , Nancy Bump 1 , Ryan Chau 1 , Bei-Ching Chuang 1 , Christopher Claiborne 1 , Larry Cohen , Kelly Connolly 1 , Matthew Duffey , Nitya Durvasula , Scott Freeze , Melissa Gallery , Katherine Galvin 1 , Jeffrey Gaulin 1 , Rachel Gershman 1 , Paul Greenspan 1 , Jessica Grieves 1 , Jianping Guo 1 , Nanda Gulavita 1 , Shumet Hailu 1 , Xingyue He 1 , Kara Hoar 1 , Yongbo Hu 1 , Zhigen Hu 1 , Mitsuhiro Ito 2 , Mi-Sook Kim 1 , Scott Weston Lane 1 , David Lok 1 , Anya Lublinsky 1 , William Mallender 1 , Charles McIntyre 1 , James Minissale 1 , Hirotake Mizutani 1 , Miho Mizutani 1 , Nina Molchinova 1 , Koji Ono 2 , Ashok Patil 1 , Mark Qian 1 , Jessica Riceberg 1 , Vaishali Shindi 1 , Michael D. Sintchak 1 , Keli Song 1 , Teresa Soucy 1 , Yana Wang 1 , He Xu 1 , Xiaofeng Yang 1 , Agatha Zawadzka 1 , Ji Zhang 1 , Sai M. Pulukuri 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-02-25 , DOI: 10.1021/acs.jmedchem.0c01491
Steven P. Langston 1 , Stephen Grossman 1 , Dylan England 1 , Roushan Afroze 1 , Neil Bence 1 , Douglas Bowman 1 , Nancy Bump 1 , Ryan Chau 1 , Bei-Ching Chuang 1 , Christopher Claiborne 1 , Larry Cohen , Kelly Connolly 1 , Matthew Duffey , Nitya Durvasula , Scott Freeze , Melissa Gallery , Katherine Galvin 1 , Jeffrey Gaulin 1 , Rachel Gershman 1 , Paul Greenspan 1 , Jessica Grieves 1 , Jianping Guo 1 , Nanda Gulavita 1 , Shumet Hailu 1 , Xingyue He 1 , Kara Hoar 1 , Yongbo Hu 1 , Zhigen Hu 1 , Mitsuhiro Ito 2 , Mi-Sook Kim 1 , Scott Weston Lane 1 , David Lok 1 , Anya Lublinsky 1 , William Mallender 1 , Charles McIntyre 1 , James Minissale 1 , Hirotake Mizutani 1 , Miho Mizutani 1 , Nina Molchinova 1 , Koji Ono 2 , Ashok Patil 1 , Mark Qian 1 , Jessica Riceberg 1 , Vaishali Shindi 1 , Michael D. Sintchak 1 , Keli Song 1 , Teresa Soucy 1 , Yana Wang 1 , He Xu 1 , Xiaofeng Yang 1 , Agatha Zawadzka 1 , Ji Zhang 1 , Sai M. Pulukuri 1
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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.
中文翻译：
TAK-981，SUMO活化酶的一流抑制剂，用于治疗癌症的发现
SUMOylation是可逆的翻译后修饰，可通过小泛素样修饰物（SUMO）蛋白质的共价附着来调节蛋白质功能。SUMOylating蛋白的过程涉及一个酶促级联反应，第一步是通过SUMO激活酶（SAE）催化的ATP依赖性过程激活SUMO蛋白。在这里，我们描述了TAK-981的鉴定，TAK-981是一种基于机理的SAE抑制剂，可形成SUMO–TAK-981加合物作为酶催化位点内的抑制物。对相关酶的选择性的优化以及加合物平均停留时间的增加对于鉴定具有有效细胞途径抑制作用并最终在临床前肿瘤模型中延长药效作用和功效的化合物至关重要，
更新日期：2021-03-11
中文翻译：
TAK-981，SUMO活化酶的一流抑制剂，用于治疗癌症的发现
SUMOylation是可逆的翻译后修饰，可通过小泛素样修饰物（SUMO）蛋白质的共价附着来调节蛋白质功能。SUMOylating蛋白的过程涉及一个酶促级联反应，第一步是通过SUMO激活酶（SAE）催化的ATP依赖性过程激活SUMO蛋白。在这里，我们描述了TAK-981的鉴定，TAK-981是一种基于机理的SAE抑制剂，可形成SUMO–TAK-981加合物作为酶催化位点内的抑制物。对相关酶的选择性的优化以及加合物平均停留时间的增加对于鉴定具有有效细胞途径抑制作用并最终在临床前肿瘤模型中延长药效作用和功效的化合物至关重要，
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