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Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer
- Source :
- Journal of medicinal chemistry. 63(22)
- 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, (3S,4S)-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 :
- Drug
Programmed cell death
media_common.quotation_subject
Allosteric regulation
Antineoplastic Agents
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Protein tyrosine phosphatase
Pharmacology
01 natural sciences
03 medical and health sciences
Mice
Dogs
Allosteric Regulation
In vivo
Neoplasms
Drug Discovery
medicine
Tumor Cells, Cultured
Animals
Humans
Enzyme Inhibitors
Gene
030304 developmental biology
media_common
0303 health sciences
Chemistry
Cancer
medicine.disease
Xenograft Model Antitumor Assays
0104 chemical sciences
Rats
PTPN11
010404 medicinal & biomolecular chemistry
Macaca fascicularis
Molecular Medicine
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 63
- Issue :
- 22
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....345804676325a445ebbb9ef600ced79a