Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:63 |
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| Enthalten in: |
Journal of medicinal chemistry - 63(2020), 22 vom: 25. Nov., Seite 13578-13594 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
LaMarche, Matthew J [VerfasserIn] |
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| Links: |
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| Themen: |
Antineoplastic Agents |
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| Anmerkungen: |
Date Completed 31.12.2020 Date Revised 31.12.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.0c01170 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM314828672 |
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| 100 | 1 | |a LaMarche, Matthew J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer |
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| 500 | |a Date Revised 31.12.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Enzyme Inhibitors |2 NLM | |
| 650 | 7 | |a PTPN11 protein, human |2 NLM | |
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| 700 | 1 | |a Acker, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Argintaru, Andreea |e verfasserin |4 aut | |
| 700 | 1 | |a Bauer, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Boisclair, Julie |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Homan |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Christine Hiu-Tung |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Ying-Nan |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Zhouliang |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Zhan |e verfasserin |4 aut | |
| 700 | 1 | |a Dore, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Dunstan, David |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Jianmei |e verfasserin |4 aut | |
| 700 | 1 | |a Fekkes, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Firestone, Brant |e verfasserin |4 aut | |
| 700 | 1 | |a Fodor, Michelle |e verfasserin |4 aut | |
| 700 | 1 | |a Garcia-Fortanet, Jorge |e verfasserin |4 aut | |
| 700 | 1 | |a Fortin, Pascal D |e verfasserin |4 aut | |
| 700 | 1 | |a Fridrich, Cary |e verfasserin |4 aut | |
| 700 | 1 | |a Giraldes, John |e verfasserin |4 aut | |
| 700 | 1 | |a Glick, Meir |e verfasserin |4 aut | |
| 700 | 1 | |a Grunenfelder, Denise |e verfasserin |4 aut | |
| 700 | 1 | |a Hao, Huia-Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Hentemann, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Ho, Samuel |e verfasserin |4 aut | |
| 700 | 1 | |a Jouk, Andriana |e verfasserin |4 aut | |
| 700 | 1 | |a Kang, Zhao B |e verfasserin |4 aut | |
| 700 | 1 | |a Karki, Rajesh |e verfasserin |4 aut | |
| 700 | 1 | |a Kato, Mitsunori |e verfasserin |4 aut | |
| 700 | 1 | |a Keen, Nick |e verfasserin |4 aut | |
| 700 | 1 | |a Koenig, Robert |e verfasserin |4 aut | |
| 700 | 1 | |a LaBonte, Laura R |e verfasserin |4 aut | |
| 700 | 1 | |a Larrow, Jay |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Gang |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Shumei |e verfasserin |4 aut | |
| 700 | 1 | |a Majumdar, Dyuti |e verfasserin |4 aut | |
| 700 | 1 | |a Mathieu, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Meyer, Matthew J |e verfasserin |4 aut | |
| 700 | 1 | |a Mohseni, Morvarid |e verfasserin |4 aut | |
| 700 | 1 | |a Ntaganda, Rukundo |e verfasserin |4 aut | |
| 700 | 1 | |a Palermo, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Perez, Lawrence |e verfasserin |4 aut | |
| 700 | 1 | |a Pu, Minying |e verfasserin |4 aut | |
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| 700 | 1 | |a Shultz, Michael D |e verfasserin |4 aut | |
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| 700 | 1 | |a Straub, Christopher |e verfasserin |4 aut | |
| 700 | 1 | |a Tamez, Victoriano |c Jr |e verfasserin |4 aut | |
| 700 | 1 | |a Toure, Bakary-Barry |e verfasserin |4 aut | |
| 700 | 1 | |a Towler, Christopher |e verfasserin |4 aut | |
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| 700 | 1 | |a Wang, Hongyun |e verfasserin |4 aut | |
| 700 | 1 | |a Williams, Sarah L |e verfasserin |4 aut | |
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| 700 | 1 | |a Zhang, Ji-Hu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Suzanne |e verfasserin |4 aut | |
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