Identification of an allosteric benzothiazolopyrimidone inhibitor of the oncogenic protein tyrosine phosphatase SHP2

被引：42

作者：

LaRochelle, Jonathan R. ^{[1
,2
]}

Fodor, Michelle ^{[3
]}

Ellegast, Jana M. ^{[6
,7
]}

Liu, Xiaoxi ^{[1
,2
]}

Vemulapalli, Vidyasiri ^{[1
,2
]}

Mohseni, Morvarid ^{[4
]}

Stams, Travis ^{[3
]}

Buhrlage, Sara J. ^{[1
,2
]}

Stegmaier, Kimberly ^{[6
,7
,8
]}

LaMarche, Matthew J. ^{[5
]}

Acker, Michael G. ^{[4
]}

Blacklow, Stephen C. ^{[1
,2
]}

机构：

[1] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[3] Novartis Inst Biomed Res, Ctr Prote Chem, Cambridge, MA USA

[4] Novartis Inst Biomed Res, Ctr Oncol, Cambridge, MA USA

[5] Novartis Inst Biomed Res, Ctr Global Discovery Chem, Cambridge, MA USA

[6] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[7] Boston Childrens Hosp, Boston, MA 02115 USA

[8] Broad Inst, Cambridge, MA 02142 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2017年 / 25卷 / 24期

关键词：

Drug discovery; Structural biology; Allosteric; Inhibitor; Phosphatase; SHP2; NOONAN-SYNDROME; PTPN11; CANCER; MUTATIONS; DOMAINS; ACTIVATION; SH-PTP2;

D O I：

10.1016/j.bmc.2017.10.025

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：6479 / 6485

页数：7

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