1801693-41-3Relevant articles and documents
Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer
Lamarche, Matthew J.,Acker, Michael,Argintaru, Andreea,Bauer, Daniel,Boisclair, Julie,Chan, Homan,Chen, Christine Hiu-Tung,Chen, Ying-Nan,Chen, Zhouliang,Deng, Zhan,Dore, Michael,Dunstan, David,Fan, Jianmei,Fekkes, Peter,Firestone, Brant,Fodor, Michelle,Garcia-Fortanet, Jorge,Fortin, Pascal D.,Fridrich, Cary,Giraldes, John,Glick, Meir,Grunenfelder, Denise,Hao, Huia-Xiang,Hentemann, Martin,Ho, Samuel,Jouk, Andriana,Kang, Zhao B.,Karki, Rajesh,Kato, Mitsunori,Keen, Nick,Koenig, Robert,Labonte, Laura R.,Larrow, Jay,Liu, Gang,Liu, Shumei,Majumdar, Dyuti,Mathieu, Simon,Meyer, Matthew J.,Mohseni, Morvarid,Ntaganda, Rukundo,Palermo, Mark,Perez, Lawrence,Pu, Minying,Ramsey, Timothy,Reilly, John,Sarver, Patrick,Sellers, William R.,Sendzik, Martin,Shultz, Michael D.,Slisz, Joanna,Slocum, Kelly,Smith, Troy,Spence, Stanley,Stams, Travis,Straub, Christopher,Tamez, Victoriano,Toure, Bakary-Barry,Towler, Christopher,Wang, Ping,Wang, Hongyun,Williams, Sarah L.,Yang, Fan,Yu, Bing,Zhang, Ji-Hu,Zhu, Suzanne
supporting information, p. 13578 - 13594 (2021/01/01)
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.
1-PYRIDAZIN-/TRIAZIN-3-YL-PIPER(-AZINE)/IDINE/PYROLIDINE DERIVATIVES AND COMPOSITIONS THEREOF FOR INHIBITING THE ACTIVITY OF SHP2
-
Paragraph 0251, (2017/08/07)
The present invention relates to compounds of formula I: in which m, Y1, Y2, Y3, R1, R2a, R2b, R3a, R3b, R4a, R4b, R5a and R5b are defined in the Summary of the Invention; capable of inhibiting the activity of SHP2. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with the aberrant activity of SHP2.
1 -PYRIDAZIN-/TRIAZIN-3-YL-PIPER(-AZINE)/IDINE/PYROLIDINE DERIVATIVES AND AND COMPOSITIONS THEREOF FOR INHIBITING THE ACTIVITY OF SHP2
-
Paragraph 00236, (2015/08/03)
The present invention relates to compounds of formula (I): in which m, p,Y1 Y2, Y3, R1, R2a, R2b, R3a, R3b, R4a, R4b, R4a and R5b are defined in the claims; capable of inhibiting the activity of SHP2. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with the aberrant activity of SHP2.
