6BN5

Non-receptor Protein Tyrosine Phosphatase SHP2 F285S in Complex with Allosteric Inhibitor JLR-2

Summary for 6BN5

• Entry DOI: 10.2210/pdb6bn5/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 11, 3-benzyl-8-chloro-2-hydroxy-4H-pyrimido[2,1-b][1,3]benzothiazol-4-one (3 entities in total)
• Functional Keywords: shp2, ptpn11, protein tyrosine phosphatase, phosphatase, allosteric inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : Q06124
• Total number of polymer chains: 2
• Total formula weight: 121235.48

Authors

Blacklow, S.C.,Stams, T.,Fodor, M.,LaRochelle, J.R. (deposition date: 2017-11-16, release date: 2017-12-13, Last modification date: 2023-10-04)

Primary citation

LaRochelle, J.R.,Fodor, M.,Ellegast, J.M.,Liu, X.,Vemulapalli, V.,Mohseni, M.,Stams, T.,Buhrlage, S.J.,Stegmaier, K.,LaMarche, M.J.,Acker, M.G.,Blacklow, S.C.
Identification of an allosteric benzothiazolopyrimidone inhibitor of the oncogenic protein tyrosine phosphatase SHP2.
Bioorg. Med. Chem., 25:6479-6485, 2017

PubMed Abstract: The PTPN11 oncogene encodes the cytoplasmic protein tyrosine phosphatase SHP2, which, through its role in multiple signaling pathways, promotes the progression of hematological malignancies and other cancers. Here, we employ high-throughput screening to discover a lead chemical scaffold, the benzothiazolopyrimidones, that allosterically inhibits this oncogenic phosphatase by simultaneously engaging the C-SH2 and PTP domains. We improved our lead to generate an analogue that better suppresses SHP2 activity in vitro. Suppression of Erk phopsphorylation by the lead compound is also consistent with SHP2 inhibition in AML cells. Our findings provide an alternative starting point for therapeutic intervention and will catalyze investigations into the relationship between SHP2 conformational regulation, activity, and disease progression.

PubMed: 29089257
DOI: 10.1016/j.bmc.2017.10.025

Experimental method

X-RAY DIFFRACTION (2.22 Å)