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6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors

Journal Article · · Journal of Medicinal Chemistry
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  1. Novartis Pharmaceuticals, Cambridge, MA (United States)
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Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator because of its role in the programmed cell death PD-L1/PD-1 pathway. In the preceding manuscript, we described the optimization of a fused, bicyclic screening hit for potency, selectivity, and physicochemical properties in order to further expand the chemical diversity of allosteric SHP2 inhibitors. In this manuscript, we describe the further expansion of our approach, morphing the fused, bicyclic system into a novel monocyclic pyrimidinone scaffold through our understanding of SAR and use of structure-based design. These studies led to the identification of SHP394 (1), an orally efficacious inhibitor of SHP2, with high lipophilic efficiency, improved potency, and enhanced pharmacokinetic properties. We also report other pyrimidinone analogues with favorable pharmacokinetic and potency profiles. Overall, this work improves upon our previously described allosteric inhibitors and exemplifies and extends the range of permissible chemical templates that inhibit SHP2 via the allosteric mechanism.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
Industrial Macromolecular Crystallography Association; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1503705
Journal Information:
Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 4 Vol. 62; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (38)

Inhibitors of Protein Tyrosine Phosphatases: Next-Generation Drugs? journal June 2005
Selective Inhibitors of the Protein Tyrosine Phosphatase SHP2 Block Cellular Motility and Growth of Cancer Cells in vitro and in vivo journal April 2015
Fluorogenic Substrates Based on Fluorinated Umbelliferones for Continuous Assays of Phosphatases and β-Galactosidases journal August 1999
The tyrosine phosphatase Shp2 (PTPN11) in cancer journal February 2008
Rational design of allosteric-inhibition sites in classical protein tyrosine phosphatases journal June 2015
Identification of an allosteric benzothiazolopyrimidone inhibitor of the oncogenic protein tyrosine phosphatase SHP2 journal December 2017
Setting expectations in molecular optimizations: Strengths and limitations of commonly used composite parameters journal November 2013
Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11 -Associated Juvenile Myelomonocytic Leukemia journal October 2015
Identification of demethylincisterol A 3 as a selective inhibitor of protein tyrosine phosphatase Shp2 journal January 2017
Crystal Structure of the Tyrosine Phosphatase SHP-2 journal February 1998
The ‘Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling journal June 2003
Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine phosphatase SHP-2 journal March 1998
Structural and Functional Consequences of Three Cancer-Associated Mutations of the Oncogenic Phosphatase SHP2 journal April 2016
Applications of Fluorine in Medicinal Chemistry journal July 2015
Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor journal July 2016
Allosteric Inhibitors of SHP2 with Therapeutic Potential for Cancer Treatment journal December 2017
Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors journal January 2019
Dual Allosteric Inhibition of SHP2 Phosphatase journal January 2018
Selective Detection of Allosteric Phosphatase Inhibitors journal April 2013
A Comparison of Physiochemical Property Profiles of Development and Marketed Oral Drugs journal March 2003
Design and Synthesis of Pyrimidinone and Pyrimidinedione Inhibitors of Dipeptidyl Peptidase IV journal January 2011
Discovery of Raltegravir, a Potent, Selective Orally Bioavailable HIV-Integrase Inhibitor for the Treatment of HIV-AIDS Infection journal September 2008
Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases journal June 2016
Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction journal January 2014
Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia journal April 2003
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome journal November 2001
The influence of drug-like concepts on decision-making in medicinal chemistry journal November 2007
Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors journal January 2008
Discovery of a Novel Inhibitor of the Protein Tyrosine Phosphatase Shp2 journal December 2015
Protein tyrosine phosphatase function: the substrate perspective journal January 2007
XDS journal January 2010
Features and development of Coot journal March 2010
Discovery of a Novel Shp2 Protein Tyrosine Phosphatase Inhibitor journal May 2006
Activating Mutations of the Noonan Syndrome-Associated SHP2/PTPN11 Gene in Human Solid Tumors and Adult Acute Myelogenous Leukemia journal December 2004
PD-1/SHP-2 Inhibits Tc1/Th1 Phenotypic Responses and the Activation of T Cells in the Tumor Microenvironment journal December 2014
PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase journal October 2006
Targeting Protein Tyrosine Phosphatases for Anticancer Drug Discovery journal June 2010
Targeting protein tyrosine phosphatase SHP2 for therapeutic intervention journal August 2014

Cited By (3)

Resistance to allosteric SHP2 inhibition in FGFR-driven cancers through rapid feedback activation of FGFR journal January 2020
Design, Synthesis, and In Vitro Activity of Pyrazine Compounds journal December 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

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Amines
Inhibitors
Peptides and proteins
Rodent models
Selectivity