SHP2 is a protein tyrosine phosphatase (PTP) that can regulate the tyrosine phosphorylation level. Overexpression of SHP2 will promote the development of cancer diseases, so SHP2 has become one of the popular targets for the treatment of cancer. Studies have reported that both SHP099 and SHP844 are inhibitors of SHP2 and bind to different allosteric sites 1 and 2, respectively. Studies have shown that combining SHP099 with SHP844 will enhance pharmacological pathway inhibition in cells. This study uses molecular dynamic simulations to explore the dual allosteric targeted inhibition mechanism. The result shows that the residues THR108-TRP112 (allosteric site 1) move to LEU236-GLN245 (αB-αC link loop in PTP domain) , the residues of GLN79-GLN87 (allosteric site 2) get close to LEU262-GLN269 (αA-αB link loop in PTP domain) and HIS458-ARG465 (P-loop) come near to ARG501-THR507 (Q-loop) in SHP2-SHP099-SHP844 system, which makes the “inactive conformation” more stable and prevents the substrate from entering the catalytic site. Meanwhile, residue GLU110 (allosteric site 1), ARG265 (allosteric site 2), and ARG501 (Q-loop) are speculated to be the key residues that causing the SHP2 protein in auto-inhibition conformation. It is hoped that this study will provide clues for the development of the dual allosteric targeted inhibition of SHP2.

SHP2 是一种蛋白质酪氨酸磷酸酶 (PTP)，可调节酪氨酸磷酸化水平。SHP2的过度表达会促进癌症疾病的发展，因此SHP2已成为治疗癌症的热门靶点之一。研究报告称，SHP099 和 SHP844 都是 SHP2 的抑制剂，分别与不同的变构位点 1 和 2 结合。研究表明，将 SHP099 与 SHP844 结合将增强细胞中的药理途径抑制作用。本研究使用分子动力学模拟来探索双重变构靶向抑制机制。结果表明残基 THR108-TRP112（变构位点 1）移动到 LEU236-GLN245（PTP 结构域中的αB-αC 连接环），GLN79-GLN87（变构位点 2）的残基接近 LEU262-GLN269（PTP 结构域中的αA-αB 连接环）和 HIS458-ARG465（P 环）接近 SHP2-中的 ARG501-THR507（Q 环） SHP099-SHP844体系，使“非活性构象”更加稳定，防止底物进入催化位点。同时，残基 GLU110（变构位点 1）、ARG265（变构位点 2）和 ARG501（Q 环）被推测是导致 SHP2 蛋白处于自抑制构象的关键残基。希望本研究能为SHP2双重变构靶向抑制的发展提供线索。ARG265（变构位点 2）和 ARG501（Q 环）被推测是导致 SHP2 蛋白处于自抑制构象的关键残基。希望本研究能为SHP2双重变构靶向抑制的发展提供线索。ARG265（变构位点 2）和 ARG501（Q 环）被推测是导致 SHP2 蛋白处于自抑制构象的关键残基。希望本研究能为SHP2双重变构靶向抑制的发展提供线索。