Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China.
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Mol Divers. 2022 Jun;26(3):1567-1580. doi: 10.1007/s11030-021-10286-4. Epub 2021 Aug 2.
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 是一种蛋白酪氨酸磷酸酶（PTP），可调节酪氨酸磷酸化水平。SHP2 的过表达会促进癌症的发展，因此 SHP2 已成为癌症治疗的热门靶点之一。研究报道，SHP099 和 SHP844 均为 SHP2 的抑制剂，分别与不同的别构位点 1 和 2 结合。研究表明，将 SHP099 与 SHP844 联合使用可增强细胞内的药理学途径抑制作用。本研究采用分子动力学模拟方法，探讨了双重别构靶向抑制机制。结果表明，残基 THR108-TRP112（别构位点 1）移动到 LEU236-GLN245（PTP 结构域中的αB-αC 连接环），残基 GLN79-GLN87（别构位点 2）靠近 LEU262-GLN269（PTP 结构域中的αA-αB 连接环）和 HIS458-ARG465（P-环）靠近 ARG501-THR507（Q-环），使 SHP2-SHP099-SHP844 系统中的“无活性构象”更加稳定，并阻止底物进入催化位点。同时，推测残基 GLU110（别构位点 1）、ARG265（别构位点 2）和 ARG501（Q-环）是导致 SHP2 蛋白处于自动抑制构象的关键残基。希望本研究能为 SHP2 的双重别构靶向抑制开发提供线索。
