Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor

被引：221

作者：

Fortanet, Jorge Garcia ^{[1
]}

Chen, Christine Hiu-Tung ^{[1
]}

Chen, Ying-Nan P. ^{[2
]}

Chen, Zhouliang ^{[1
]}

Deng, Zhan ^{[3
]}

Firestone, Brant ^{[2
]}

Fekkes, Peter ^{[3
]}

Fodor, Michelle ^{[3
]}

Fortin, Pascal D. ^{[2
]}

Fridrich, Cary ^{[1
]}

Grunenfelder, Denise ^{[1
]}

Ho, Samuel ^{[3
]}

Kang, Zhao B. ^{[3
]}

Karki, Rajesh ^{[1
]}

Kato, Mitsunori ^{[1
]}

Keen, Nick ^{[2
]}

LaBonte, Laura R. ^{[4
]}

Larrow, Jay ^{[1
]}

Lenoir, Francois ^{[1
]}

Liu, Gang ^{[1
]}

Liu, Shumei ^{[2
]}

Lombardo, Franco ^{[4
]}

Majumdar, Dyuti ^{[1
]}

Meyer, Matthew J. ^{[2
]}

Palermo, Mark ^{[1
]}

Perez, Lawrence ^{[1
]}

Pu, Minying ^{[2
]}

Ramsey, Timothy ^{[1
]}

Sellers, William R. ^{[2
]}

Shultz, Michael D. ^{[1
]}

Stams, Travis ^{[3
]}

Towler, Christopher ^{[5
]}

Wang, Ping ^{[2
]}

Williams, Sarah L. ^{[1
]}

Zhang, Ji-Hu ^{[3
]}

LaMarche, Matthew J. ^{[1
]}

机构：

[1] Novartis Pharmaceut, Global Discovery Chem, 250 Massachusetts Ave, Cambridge, MA 02139 USA

[2] Novartis Pharmaceut, Oncol Dis Area, 250 Massachusetts Ave, Cambridge, MA 02139 USA

[3] Novartis Pharmaceut, Ctr Prote Chem, 250 Massachusetts Ave, Cambridge, MA 02139 USA

[4] Novartis Pharmaceut, Metab & Pharmacokinet, Novartis Inst Biomed Res, 250 Massachusetts Ave, Cambridge, MA 02139 USA

[5] Novartis Pharmaceut, Chem & Pharmaceut Profiling, 250 Massachusetts Ave, Cambridge, MA 02139 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 17期

关键词：

PROTEIN-TYROSINE PHOSPHATASES; ACUTE MYELOID-LEUKEMIA; PTPN11; CANCER; DESIGN; MUTATIONS;

D O I：

10.1021/acs.jmedchem.6b00680

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our labs, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the auto-inhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition and several new protein-ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, I), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.

引用

页码：7773 / 7782

页数：10

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