6MDD

Non-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitor Imidazo-pyridine 24

Summary for 6MDD

• Entry DOI: 10.2210/pdb6mdd/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 11, 5-[(2,3-dichlorophenyl)sulfanyl]-3H-imidazo[4,5-b]pyridin-2-amine, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: shp2, ptpn11, protein tyrosine phosphatase, phosphatase, allosteric inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 121482.39

Authors

Fodor, M.,Stams, T. (deposition date: 2018-09-04, release date: 2019-02-13, Last modification date: 2023-10-11)

Primary citation

Bagdanoff, J.T.,Chen, Z.,Acker, M.,Chen, Y.N.,Chan, H.,Dore, M.,Firestone, B.,Fodor, M.,Fortanet, J.,Hentemann, M.,Kato, M.,Koenig, R.,LaBonte, L.R.,Liu, S.,Mohseni, M.,Ntaganda, R.,Sarver, P.,Smith, T.,Sendzik, M.,Stams, T.,Spence, S.,Towler, C.,Wang, H.,Wang, P.,Williams, S.L.,LaMarche, M.J.
Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors.
J. Med. Chem., 62:1781-1792, 2019

PubMed Abstract: SHP2 is a nonreceptor protein tyrosine phosphatase within the mitogen-activated protein kinase (MAPK) pathway controlling cell growth, differentiation, and oncogenic transformation. SHP2 also participates in the programed cell death pathway (PD-1/PD-L1) governing immune surveillance. Small-molecule inhibition of SHP2 has been widely investigated, including in our previous reports describing SHP099 (2), which binds to a tunnel-like allosteric binding site. To broaden our approach to allosteric inhibition of SHP2, we conducted additional hit finding, evaluation, and structure-based scaffold morphing. These studies, reported here in the first of two papers, led to the identification of multiple 5,6-fused bicyclic scaffolds that bind to the same allosteric tunnel as 2. We demonstrate the structural diversity permitted by the tunnel pharmacophore and culminated in the identification of pyrazolopyrimidinones (e.g., SHP389, 1) that modulate MAPK signaling in vivo. These studies also served as the basis for further scaffold morphing and optimization, detailed in the following manuscript.

PubMed: 30688462
DOI: 10.1021/acs.jmedchem.8b01725

Experimental method

X-RAY DIFFRACTION (2.05 Å)