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Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer.

Authors :
LaMarche MJ
Acker M
Argintaru A
Bauer D
Boisclair J
Chan H
Chen CH
Chen YN
Chen Z
Deng Z
Dore M
Dunstan D
Fan J
Fekkes P
Firestone B
Fodor M
Garcia-Fortanet J
Fortin PD
Fridrich C
Giraldes J
Glick M
Grunenfelder D
Hao HX
Hentemann M
Ho S
Jouk A
Kang ZB
Karki R
Kato M
Keen N
Koenig R
LaBonte LR
Larrow J
Liu G
Liu S
Majumdar D
Mathieu S
Meyer MJ
Mohseni M
Ntaganda R
Palermo M
Perez L
Pu M
Ramsey T
Reilly J
Sarver P
Sellers WR
Sendzik M
Shultz MD
Slisz J
Slocum K
Smith T
Spence S
Stams T
Straub C
Tamez V Jr
Toure BB
Towler C
Wang P
Wang H
Williams SL
Yang F
Yu B
Zhang JH
Zhu S
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.

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