29MM

Crystal structure of SHP2 in complex with I-0436650

This is a non-PDB format compatible entry.

Summary for 29MM

• Entry DOI: 10.2210/pdb29mm/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 11, (4S)-1'-[5-(3-chloranyl-2-pyrazol-1-yl-pyridin-4-yl)sulfanylpyrazin-2-yl]spiro[4,6-dihydropyrrolo[1,2-b]pyrazole-5,4'-piperidine]-4-amine, SULFATE ION, ... (6 entities in total)
• Functional Keywords: inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 121774.14

Authors

Petrocchi, A.,Ciammaichella, A. (deposition date: 2026-03-23, release date: 2026-08-12, Last modification date: 2026-08-26)

Primary citation

Ciammaichella, A.,Puca, F.,Fabbrini, D.,Randazzo, P.,Rossetti, I.,Sferrazza, A.,Ferrigno, F.,Grillo, A.,Torrente, E.,Iaccarino, C.,Amaudrut, J.,Cellucci, A.,Di Marco, A.,Palombo, S.,Esposito, S.,Bisbocci, M.,Orsale, M.V.,Nibbio, M.,Missineo, A.,Scalabri, F.,Fodale, V.,Pucci, V.,Alli, C.,Di Fabio, R.,Montalbetti, C.,Carugo, A.,Toniatti, C.,Petrocchi, A.
Discovery and Preclinical Characterization of I-0436650, a Selective SHP2 Allosteric Inhibitor for RAS-Driven Cancers.
J.Med.Chem., 69:18898-18914, 2026

PubMed Abstract: SHP2 (Src homology 2 (SH2)-containing protein tyrosine phosphatase 2) is a tyrosine phosphatase that plays a critical role in numerous physiological and pathological cellular processes, including cell proliferation, survival, and migration through the regulation of multiple signaling pathways, such as RAS-RAF-mitogen-activated protein kinase, phosphatidylinositol 3-kinase (PI3K)-AKT, Janus tyrosine kinase (JAK), and signal transducer and activator of transcription pathways (STAT) in response to cytokines and growth factors. Through extensive structure-based optimization, we identified I-0436650, a preclinical candidate with an excellent pharmacological profile. I-0436650 is a low nanomolar allosteric inhibitor of human wild-type (wt) SHP2 and strongly inhibits ERK phosphorylation in cells. It exhibits antiproliferative activity in EGFR- and RAS-dependent cell lines, suppresses tumor growth as a single agent in xenograft models, and delays tumor relapse when combined with inhibitors of the same pathway, demonstrating the potential of vertical inhibition strategies.

PubMed: 42593923
DOI: 10.1021/acs.jmedchem.6c01182

Experimental method

X-RAY DIFFRACTION (2.197 Å)