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