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

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.

• Authors: Matthew J LaMarche, Michael Acker, Andreea Argintaru, Daniel Bauer, Julie Boisclair, Homan Chan, Christine Hiu-Tung Chen, Ying-Nan Chen, Zhouliang Chen, Zhan Deng, Michael Dore, David Dunstan, Jianmei Fan, Peter Fekkes, Brant Firestone, Michelle Fodor, Jorge Garcia-Fortanet, Pascal D Fortin, Cary Fridrich, John Giraldes, Meir Glick, Denise Grunenfelder, Huia-Xiang Hao, Martin Hentemann, Samuel Ho, Andriana Jouk, Zhao B Kang, Rajesh Karki, Mitsunori Kato, Nick Keen, Robert Koenig, Laura R LaBonte, Jay Larrow, Gang Liu, Shumei Liu, Dyuti Majumdar, Simon Mathieu, Matthew J Meyer, Morvarid Mohseni, Rukundo Ntaganda, Mark Palermo, Lawrence Perez, Minying Pu, Timothy Ramsey, John Reilly, Patrick Sarver, William R Sellers, Martin Sendzik, Michael D Shultz, Joanna Slisz, Kelly Slocum, Troy Smith, Stanley Spence, Travis Stams, Christopher Straub, Victoriano Tamez Jr, Bakary-Barry Toure, Christopher Towler, Ping Wang, Hongyun Wang, Sarah L Williams, Fan Yang, Bing Yu, Ji-Hu Zhang, Suzanne Zhu
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 63 Issue 22 Pg. 13578-13594 (11 25 2020) ISSN: 1520-4804 [Electronic] United States
• PMID: 32910655 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• PTPN11 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 11

Topics

• Allosteric Regulation (drug effects, physiology)
• Animals
• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Dogs
• Enzyme Inhibitors (chemistry, pharmacology, therapeutic use)
• Humans
• Macaca fascicularis
• Mice
• Neoplasms (drug therapy, enzymology, pathology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (antagonists & inhibitors, metabolism)
• Rats
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays (methods)