Discovery and biological evaluation of vinylsulfonamide derivatives as highly potent, covalent TEAD autopalmitoylation inhibitors.,European Journal of Medicinal Chemistry

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Discovery and biological evaluation of vinylsulfonamide derivatives as highly potent, covalent TEAD autopalmitoylation inhibitors.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2019-10-09 , DOI: 10.1016/j.ejmech.2019.111767
Wenchao Lu ₁ , Jun Wang ₂ , Yong Li ₃ , Hongru Tao ₄ , Huan Xiong ₅ , Fulin Lian ₆ , Jing Gao ₇ , Hongna Ma ₈ , Tian Lu ₂ , Dan Zhang ₉ , Xiaoqing Ye ₁₀ , Hong Ding ₁₁ , Liyan Yue ₁₁ , Yuanyuan Zhang ₁₁ , Huanyu Tang ₃ , Naixia Zhang ₆ , Yaxi Yang ₃ , Hualiang Jiang ₁₂ , Kaixian Chen ₁₃ , Bing Zhou ₃ , Cheng Luo ₁₃

Affiliation

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China.
University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Department of Chemistry, College of Sciences, Shanghai University, 99 Shangda Road, Shanghai, 200444, China.
Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Department of Pharmacy, Guiyang University of Traditional Chinese Medicine, South Dong Qing Road, Guizhou, 550025, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Key Laboratory of Guizhou for Fermentation Engineering and Biomedicine, School of Pharmaceutical Sciences, Guizhou University, Guizhou, 550025, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; College of Life Sciences, Zhejiang Sci-Tech University, 928 No.2 Street, Hangzhou, 310018, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao, 266237, China.

Transcriptional enhancer associated domain family members (TEADs) are the most important downstream effectors that play the pivotal role in the development, regeneration and tissue homeostasis. Recent biochemical studies have demonstrated that TEADs could undergo autopalmitoylation that is indispensable for its function making the lipid-binding pocket an attractive target for chemical intervention. Herein, through structure-based virtual screen and rational medicinal chemistry optimization, we identified DC-TEADin02 as the most potent, selective, covalent TEAD autopalmitoylation inhibitor with the IC50 value of 197 ± 19 nM while it showed minimal effect on TEAD-YAP interaction. Further biochemical counter-screens demonstrate the specific thiol reactivity and selectivity of DC-TEADin02 over the kinase family, lipid-binding proteins and epigenetic targets. Notably, DC-TEADin02 inhibited TEADs transcription activity leading to downregulation of YAP-related downstream gene expression. Taken together, our findings proved the validity of modulating transcriptional output in the Hippo signaling pathway through irreversible chemical interventions of TEADs autopalmitoylation activity, which may serve as a qualified chemical tool for TEADs palmitoylation-related studies in the future.

中文翻译：

乙烯基磺酰胺衍生物作为高效，共价TEAD自棕榈酸酯化抑制剂的发现和生物学评估。

转录增强子相关域家族成员（TEADs）是最重要的下游效应子，在发育，再生和组织稳态中发挥关键作用。最近的生化研究表明，TEADs可能会经历自身的棕榈酰化作用，这对其功能是必不可少的，这使得脂质结合袋成为化学干预的有吸引力的靶标。在本文中，通过基于结构的虚拟筛选和合理的药物化学优化，我们确定DC-TEADin02是最有效，选择性最高的共价TEAD自戊二酰化抑制剂，IC50值为197±19 nM，而对TEAD-YAP相互作用的影响却最小。进一步的生化反筛查证明了DC-TEADin02在激酶家族中的特异性硫醇反应性和选择性，脂质结合蛋白和表观遗传学靶标。值得注意的是，DC-TEADin02抑制TEADs转录活性，从而导致YAP相关下游基因表达的下调。综上所述，我们的发现证明了通过不可逆的TEADs自身棕榈酰化活性的化学干预，在Hippo信号通路中调节转录输出的有效性，这可能会在将来成为TEAD棕榈酰化相关研究的合格化学工具。

更新日期：2019-10-09

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