GRB2 SH2 结构域单羧酸抑制剂的合成与结构表征。
Synthesis and structural characterization of a monocarboxylic inhibitor for GRB2 SH2 domain.
机构信息
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, United States.
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, United States; Department of Chemistry, University of South Florida, Tampa, FL, United States.
出版信息
Bioorg Med Chem Lett. 2021 Nov 1;51:128354. doi: 10.1016/j.bmcl.2021.128354. Epub 2021 Sep 7.
A monocarboxylic inhibitor was designed and synthesized to disrupt the protein-protein interaction (PPI) between GRB2 and phosphotyrosine-containing proteins. Biochemical characterizations show compound 7 binds with the Src homology 2 (SH2) domain of GRB2 and is more potent than EGFR phosphopeptide 14-mer. X-ray crystallographic studies demonstrate compound 7 occupies the GRB2 binding site for phosphotyrosine-containing sequences and reveal key structural features for GRB2-inhibitor binding. This compound with a -1 formal charge offers a new direction for structural optimization to generate cell-permeable inhibitors for this key protein target of the aberrant Ras-MAPK signaling cascade.
设计并合成了一种单羧酸抑制剂来破坏 GRB2 与含磷酸酪氨酸蛋白的蛋白-蛋白相互作用（PPI）。生化特性表明，化合物 7 与 GRB2 的Src 同源 2（SH2）结构域结合，并且比 EGFR 磷酸肽 14 -mer 更有效。X 射线晶体学研究表明，化合物 7 占据了 GRB2 结合含磷酸酪氨酸序列的结合位点，并揭示了 GRB2 抑制剂结合的关键结构特征。该化合物带有-1 个形式电荷，为针对异常 Ras-MAPK 信号级联的这一关键蛋白靶标生成细胞通透性抑制剂提供了新的结构优化方向。
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