7VXG

Non-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitor TK-453

Summary for 7VXG

• Entry DOI: 10.2210/pdb7vxg/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 11, 6-[4-(aminomethyl)-4-methyl-piperidin-1-yl]-3-[2,3-bis(chloranyl)phenyl]sulfanyl-pyrazin-2-amine (3 entities in total)
• Functional Keywords: protein tyrosine phosphatase, shp2, inhibitor, complex, antitumor protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 242933.55

Authors

Li, T.H.,Guo, H.T.,Ji, X.Y. (deposition date: 2021-11-12, release date: 2022-03-23, Last modification date: 2023-11-29)

Primary citation

Wang, M.,Li, T.,Ouyang, Z.,Tang, K.,Zhu, Y.,Song, C.,Sun, H.,Yu, B.,Ji, X.,Sun, Y.
SHP2 allosteric inhibitor TK-453 alleviates psoriasis-like skin inflammation in mice via inhibition of IL-23/Th17 axis.
Iscience, 25:104009-104009, 2022

PubMed Abstract: SHP2 is the first oncogenic tyrosine phosphatase encoded by , which plays a significant regulatory role in cancer and inflammation-related diseases. Although SHP2 allosteric inhibitors have been used in phase I/II clinical trials for solid tumors, whether SHP2 inhibition alleviates psoriasis remains unclear. Here we expressed and purified SHP2 related proteins, and established an enzyme activity screening system for different conformations of SHP2. We launched an iterative medicinal chemistry program and identified the lead compound, TK-453. Importantly, TK-453 possessed stronger affinity with SHP2 than SHP099, evidenced by the cocrystal structure of SHP2/TK-453, revealing that the additional aryl-S-aryl bridge in TK-453 induces a 1.8 Å shift of the dichlorophenyl ring and an approximate 20° deviation of the pyrazine ring plane relative to SHP099. Furthermore, TK-453 significantly ameliorated imiquimod-triggered skin inflammation in mice via inhibition of the IL-23/Th17 axis, proving that SHP2 is a potential therapeutic target for psoriasis.

PubMed: 35310939
DOI: 10.1016/j.isci.2022.104009

Experimental method

X-RAY DIFFRACTION (2.1 Å)