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

Authors :
Kelly Slocum
Jianmei Fan
Michael Dore
Palermo Mark G
Zhan Deng
Bakary-Barry Toure
Jorge Garcia-Fortanet
Dyuti Majumdar
Martin F. Hentemann
Nick Keen
Suzanne Zhu
Christopher Towler
Michael Shultz
William R. Sellers
Simon Mathieu
Denise Grunenfelder
Robert Koenig
Douglas C. Bauer
Shumei Liu
Jay Larrow
Victoriano Tamez
David Dunstan
Andreea Argintaru
Timothy Michael Ramsey
Zhouliang Chen
Gang Liu
Ying-Nan Chen
Rukundo Ntaganda
Bing Yu
Joanna Slisz
Hongyun Wang
Pascal D. Fortin
Christopher Sean Straub
Ji-Hu Zhang
Ping Wang
Laura R. LaBonte
Mitsunori Kato
Matthew J. Meyer
Fan Yang
Patrick James Sarver
Samuel B. Ho
Brant Firestone
Rajesh Karki
John F. Reilly
Troy Smith
Ho Man Chan
Cary Fridrich
John William Giraldes
Julie Boisclair
Chen Christine Hiu-Tung
Meir Glick
Zhao B. Kang
Morvarid Mohseni
Lawrence Blas Perez
Michael G. Acker
Sarah Williams
Matthew J. LaMarche
Martin Sendzik
Michelle Fodor
Huia-Xiang Hao
Peter Fekkes
Minying Pu
Travis Stams
Stanley Spence
Andriana Jouk
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.

Details

ISSN :
15204804
Volume :
63
Issue :
22
Database :
OpenAIRE
Journal :
Journal of medicinal chemistry
Accession number :
edsair.doi.dedup.....345804676325a445ebbb9ef600ced79a