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

被引：130

作者：

LaMarche, Matthew J. ^{[2
]}

Acker, Michael ^{[1
]}

Argintaru, Andreea ^{[2
]}

Bauer, Daniel ^{[3
]}

Boisclair, Julie ^{[3
]}

Chan, Homan ^{[1
]}

Chen, Christine Hiu-Tung ^{[2
]}

Chen, Ying-Nan ^{[1
]}

Chen, Zhouliang ^{[2
]}

Deng, Zhan ^{[4
]}

Dore, Michael ^{[2
]}

Dunstan, David ^{[2
]}

Fan, Jianmei ^{[2
]}

Fekkes, Peter ^{[4
]}

Firestone, Brant ^{[1
]}

Fodor, Michelle ^{[4
]}

Garcia-Fortanet, Jorge ^{[2
]}

Fortin, Pascal D. ^{[1
]}

Fridrich, Cary ^{[2
]}

Giraldes, John ^{[2
]}

Glick, Meir ^{[4
]}

Grunenfelder, Denise ^{[2
]}

Hao, Huia-Xiang ^{[1
]}

Hentemann, Martin ^{[1
]}

Ho, Samuel ^{[4
]}

Jouk, Andriana ^{[2
]}

Kang, Zhao B. ^{[4
]}

Karki, Rajesh ^{[2
]}

Kato, Mitsunori ^{[2
]}

Keen, Nick ^{[1
]}

Koenig, Robert ^{[2
]}

LaBonte, Laura R. ^{[5
]}

Larrow, Jay ^{[2
]}

Liu, Gang ^{[2
]}

Liu, Shumei ^{[1
]}

Majumdar, Dyuti ^{[2
]}

Mathieu, Simon ^{[2
]}

Meyer, Matthew J. ^{[1
]}

Mohseni, Morvarid ^{[1
]}

Ntaganda, Rukundo ^{[2
]}

Palermo, Mark ^{[2
]}

Perez, Lawrence ^{[2
]}

Pu, Minying ^{[1
]}

Ramsey, Timothy ^{[2
]}

Reilly, John ^{[2
]}

Sarver, Patrick ^{[2
]}

Sellers, William R. ^{[1
]}

Sendzik, Martin ^{[2
]}

Shultz, Michael D. ^{[2
]}

Slisz, Joanna ^{[1
]}

机构：

[1] Novartis Pharmaceut, Oncol Dis Area, Cambridge, MA 02139 USA

[2] Novartis Pharmaceut, Global Discovery Chem, Cambridge, MA 02139 USA

[3] Novartis Pharmaceut, Preclin Safety Novartis Inst Biomed Res, Cambridge, MA 02139 USA

[4] Novartis Pharmaceut, Prot Struct Grp, Cambridge, MA 02139 USA

[5] Novartis Pharmaceut, Metab & Pharmacokinet, Cambridge, MA 02139 USA

[6] Novartis Pharmaceut, Chem & Pharmaceut Profiling, Cambridge, MA 02139 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 22期

关键词：

TYROSINE-PHOSPHATASE SHP2; PTPN11; MUTATIONS; ALCOHOLS;

D O I：

10.1021/acs.jmedchem.0c01170

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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 TN0155, (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.

引用

页码：13578 / 13594

页数：17

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