7R75

Structure of human SHP2 in complex with compound 16

7R75 の概要

• エントリーDOI: 10.2210/pdb7r75/pdb
• 関連するPDBエントリー: 6WU8
• 分子名称: Tyrosine-protein phosphatase non-receptor type 11, 6-(4-amino-4-methylpiperidin-1-yl)-3-(3-chlorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (2 entities in total)
• 機能のキーワード: phosphatase, inhibitor, shp2, allosteric, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 61850.22

構造登録者

Leonard, P.G.,Cross, J. (登録日: 2021-06-24, 公開日: 2021-10-27, 最終更新日: 2023-10-18)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.83 Å)