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

Journal Article · · Journal of Medicinal Chemistry
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  1. Novartis Pharmaceuticals, Cambridge, MA (United States)
+ Show Author Affiliations
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 programmed cell death pathway (PD-1/PD-L1). Because it is 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 laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited 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. Furthermore, these studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1404987
Journal Information:
Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 17 Vol. 59; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (28)

Selective inhibition of leukemia-associated SHP2E69K mutant by the allosteric SHP2 inhibitor SHP099 journal January 2018
Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2 journal October 2018
Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition journal October 2018
Strategies for monitoring and combating resistance to combination kinase inhibitors for cancer therapy journal April 2017
Resistance to allosteric SHP2 inhibition in FGFR-driven cancers through rapid feedback activation of FGFR journal January 2020
Proteinaceous Regulators and Inhibitors of Protein Tyrosine Phosphatases journal February 2018
Design, Synthesis, and In Vitro Activity of Pyrazine Compounds journal December 2019
Interrogating Protein Phosphatases with Chemical Activity Probes journal March 2018
Clinical significance and biological function of WD repeat domain 54 as an oncogene in colorectal cancer journal December 2018
Critical individual roles of the BCR and FGFR1 kinase domains in BCR‐FGFR1‐driven stem cell leukemia/lymphoma syndrome journal October 2019
Structure based design of selective SHP2 inhibitors by De novo design, synthesis and biological evaluation journal July 2019
SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors journal March 2018
RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers journal August 2018
Inducing and exploiting vulnerabilities for the treatment of liver cancer journal October 2019
Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition journal May 2018
SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo journal May 2018
Biologically active marine natural products and their molecular targets discovered using a chemical genetics approach journal January 2020
Identification and structure–function analyses of an allosteric inhibitor of the tyrosine phosphatase PTPN22 journal April 2019
Probing the acting mode and advantages of RMC-4550 as an Src-homology 2 domain-containing protein tyrosine phosphatase (SHP2) inhibitor at molecular level through molecular docking and molecular dynamics journal May 2019
Investigating the reason for loss-of-function of Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) caused by Y279C mutation through molecular dynamics simulation journal July 2019
Design, synthesis, biological evaluation, common feature pharmacophore model and molecular dynamics simulation studies of ethyl 4-(phenoxymethyl)-2-phenylthiazole-5-carboxylate as Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors journal February 2020
Targeting PDGFRα-activated glioblastoma through specific inhibition of SHP-2–mediated signaling journal June 2019
Upregulated SHP‐2 expression in the epileptogenic zone of temporal lobe epilepsy and various effects of SHP099 treatment on a pilocarpine model journal August 2019
Synthetic lethality of TNK2 inhibition in PTPN11-mutant leukemia journal July 2018
Probing the acting mode and advantages of RMC-4550 as an Src-homology 2 domain-containing protein tyrosine phosphatase (SHP2) inhibitor at molecular level through molecular docking and molecular dynamics text January 2019
Probing the acting mode and advantages of RMC-4550 as an Src-homology 2 domain-containing protein tyrosine phosphatase (SHP2) inhibitor at molecular level through molecular docking and molecular dynamics text January 2019
Investigating the reason for loss-of-function of Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) caused by Y279C mutation through molecular dynamics simulation text January 2019
Investigating the reason for loss-of-function of Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) caused by Y279C mutation through molecular dynamics simulation text January 2019

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES
amines
conformation
inhibition
inhibitors
peptides and proteins