5XZR

The atomic structure of SHP2 E76A mutant in complex with allosteric inhibitor 9b

Summary for 5XZR

• Entry DOI: 10.2210/pdb5xzr/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 11, 4-(3-phenylphenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3-thiazol-2-amine (3 entities in total)
• Functional Keywords: phosphatase, sh2 domain, allosteric inhibitor, cancer, signaling protein, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : Q06124
• Total number of polymer chains: 1
• Total formula weight: 64242.55

Authors

Li, D.,Xie, J.,Zhu, J.,Liu, C. (deposition date: 2017-07-13, release date: 2017-12-13, Last modification date: 2023-11-22)

Primary citation

Xie, J.,Si, X.,Gu, S.,Wang, M.,Shen, J.,Li, H.,Shen, J.,Li, D.,Fang, Y.,Liu, C.,Zhu, J.
Allosteric Inhibitors of SHP2 with Therapeutic Potential for Cancer Treatment.
J. Med. Chem., 60:10205-10219, 2017

PubMed Abstract: SHP2, a cytoplasmic protein-tyrosine phosphatase encoded by the PTPN11 gene, is involved in multiple cell signaling processes including Ras/MAPK and Hippo/YAP pathways. SHP2 has been shown to contribute to the progression of a number of cancer types including leukemia, gastric, and breast cancers. It also regulates T-cell activation by interacting with inhibitory immune checkpoint receptors such as the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA). Thus, SHP2 inhibitors have drawn great attention by both inhibiting tumor cell proliferation and activating T cell immune responses toward cancer cells. In this study, we report the identification of an allosteric SHP2 inhibitor 1-(4-(6-bromonaphthalen-2-yl)thiazol-2-yl)-4-methylpiperidin-4-amine (23) that locks SHP2 in a closed conformation by binding to the interface of the N-terminal SH2, C-terminal SH2, and phosphatase domains. Compound 23 suppresses MAPK signaling pathway and YAP transcriptional activity and shows antitumor activity in vivo. The results indicate that allosteric inhibition of SHP2 could be a feasible approach for cancer therapy.

PubMed: 29155585
DOI: 10.1021/acs.jmedchem.7b01520

Experimental method

X-RAY DIFFRACTION (2.8 Å)