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Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2020 Nov 25; Vol. 63 (22), pp. 13578-13594. Date of Electronic Publication: 2020 Sep 24. - Publication Year :
- 2020
-
Abstract
- SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein-ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3 S ,4 S )-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine ( 1 ), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.
- Subjects :
- Allosteric Regulation drug effects
Allosteric Regulation physiology
Animals
Antineoplastic Agents therapeutic use
Dogs
Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacology
Enzyme Inhibitors therapeutic use
Humans
Macaca fascicularis
Mice
Neoplasms drug therapy
Neoplasms pathology
Rats
Tumor Cells, Cultured
Xenograft Model Antitumor Assays methods
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Neoplasms enzymology
Protein Tyrosine Phosphatase, Non-Receptor Type 11 antagonists & inhibitors
Protein Tyrosine Phosphatase, Non-Receptor Type 11 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 63
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32910655
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.0c01170