8WX7

Crystal structure of SHP2 in complex with JAB-3186

Summary for 8WX7

• Entry DOI: 10.2210/pdb8wx7/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 11, 1,2-ETHANEDIOL, (5~{S})-1'-[6-azanyl-5-(2-azanyl-3-chloranyl-pyridin-4-yl)sulfanyl-pyrazin-2-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-5-amine, ... (6 entities in total)
• Functional Keywords: phosphatase cancer, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 123191.41

Authors

Ma, C.,Gao, P.,Kang, D.,Han, H.,Sun, X.,Zhang, W.,Qian, D.,Wang, Y.,Long, W. (deposition date: 2023-10-27, release date: 2024-08-14, Last modification date: 2024-09-04)

Primary citation

Ma, C.,Kang, D.,Gao, P.,Zhang, W.,Wu, X.,Xu, Z.,Han, H.,Zhang, L.,Cai, Y.,Wang, Y.,Wang, Y.,Long, W.
Discovery of JAB-3312, a Potent SHP2 Allosteric Inhibitor for Cancer Treatment.
J.Med.Chem., 67:13534-13549, 2024

PubMed Abstract: As an oncogenic phosphatase, SHP2 acts as a converging node in the RTK-RAS-MAPK signaling pathway in cancer cells and suppresses antitumor immunity by passing signals downstream of PD-1. Here, we utilized the extra druggable pocket outside the previously identified SHP2 allosteric tunnel site by the (6,5 fused), 6 spirocyclic system. The optimized compound, , exhibited a SHP2 binding of 0.37 nM, SHP2 enzymatic IC of 1.9 nM, KYSE-520 antiproliferative IC of 7.4 nM and p-ERK inhibitory IC of 0.23 nM. For , an oral dose of 1.0 mg/kg QD was sufficient to achieve 95% TGI in KYSE-520 xenograft model of mouse. was well-tolerated in animal models, and a close correlation was observed between the plasma concentration of and the p-ERK inhibition in tumors. Currently, is undergoing clinical trials as a potential anticancer agent.

PubMed: 39110625
DOI: 10.1021/acs.jmedchem.4c00360

Experimental method

X-RAY DIFFRACTION (2.02 Å)