7R7I

Structure of human SHP2 in complex with compound 27

Summary for 7R7I

• Entry DOI: 10.2210/pdb7r7i/pdb
• Related: 6WU8
• Descriptor: Tyrosine-protein phosphatase non-receptor type 11, [3-(4-amino-4-methylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol (3 entities in total)
• Functional Keywords: phosphatase, inhibitor, shp2, allosteric, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 123745.39

Authors

Leonard, P.G.,Cross, J. (deposition date: 2021-06-24, release date: 2021-10-27, Last modification date: 2023-10-18)

Primary citation

Czako, B.,Sun, Y.,McAfoos, T.,Cross, J.B.,Leonard, P.G.,Burke, J.P.,Carroll, C.L.,Feng, N.,Harris, A.L.,Jiang, Y.,Kang, Z.,Kovacs, J.J.,Mandal, P.,Meyers, B.A.,Mseeh, F.,Parker, C.A.,Yu, S.S.,Williams, C.C.,Wu, Q.,Di Francesco, M.E.,Draetta, G.,Heffernan, T.,Marszalek, J.R.,Kohl, N.E.,Jones, P.
Discovery of 6-[(3 S ,4 S )-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor.
J.Med.Chem., 64:15141-15169, 2021

PubMed Abstract: Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal pharmacokinetic (PK) profile. Hypothesis-driven scaffold optimization led us to a series of pyrazolopyrazines with excellent PK properties across species but a narrow human Ether-à-go-go-Related Gene (hERG) window. Subsequent optimization of properties led to the discovery of the pyrimidinone series, in which multiple members possessed excellent potency, optimal PK across species, and no off-target activities including no hERG liability up to 100 μM. Importantly, compound (IACS-15414) potently suppressed the mitogen-activated protein kinase (MAPK) pathway signaling and tumor growth in RTK-activated and KRAS xenograft models

PubMed: 34643390
DOI: 10.1021/acs.jmedchem.1c01132

Experimental method

X-RAY DIFFRACTION (2.85 Å)