Discovery of 9-(6-aminopyridin-3-yl)-1-(3- (trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective and orally available mTOR inhibitor for treatment of cancer
The mTOR mediated PI3K/AKT/mTOR signal transduction pathway has been demonstrated to play a key role in a broad spectrum of cancers. Starting from the mTOR selective inhibitor 1 (Torin1), a focused medicinal chemistry effort led to the discovery of an improved mTOR inhibitor 3 (Torin2), which posses...
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| Format: | Article |
| Language: | en_US |
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American Chemical Society (ACS)
2012
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| Online Access: | http://hdl.handle.net/1721.1/74550 https://orcid.org/0000-0002-1446-7256 |
| _version_ | 1826201855207669760 |
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| author | Liu, Qingsong Wang, Jinhua Kang, Seong A. Thoreen, Carson C. Hur, Wooyoung Ahmed, Tausif Gray, Nathanael S. Sabatini, David |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Liu, Qingsong Wang, Jinhua Kang, Seong A. Thoreen, Carson C. Hur, Wooyoung Ahmed, Tausif Gray, Nathanael S. Sabatini, David |
| author_sort | Liu, Qingsong |
| collection | MIT |
| description | The mTOR mediated PI3K/AKT/mTOR signal transduction pathway has been demonstrated to play a key role in a broad spectrum of cancers. Starting from the mTOR selective inhibitor 1 (Torin1), a focused medicinal chemistry effort led to the discovery of an improved mTOR inhibitor 3 (Torin2), which possesses an EC[subscript 50] of 0.25 nM for inhibiting cellular mTOR activity. Compound 3 exhibited 800-fold selectivity over PI3K (EC[subscript 50]: 200 nM) and over 100-fold binding selectivity relative to 440 other protein kinases. Compound 3 has significantly improved bioavailability (54%), metabolic stability, and plasma exposure relative to compound 1. |
| first_indexed | 2024-09-23T11:58:15Z |
| format | Article |
| id | mit-1721.1/74550 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:58:15Z |
| publishDate | 2012 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/745502022-10-01T07:20:14Z Discovery of 9-(6-aminopyridin-3-yl)-1-(3- (trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective and orally available mTOR inhibitor for treatment of cancer Liu, Qingsong Wang, Jinhua Kang, Seong A. Thoreen, Carson C. Hur, Wooyoung Ahmed, Tausif Gray, Nathanael S. Sabatini, David Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Koch Institute for Integrative Cancer Research at MIT Kang, Seong A. Sabatini, David M. The mTOR mediated PI3K/AKT/mTOR signal transduction pathway has been demonstrated to play a key role in a broad spectrum of cancers. Starting from the mTOR selective inhibitor 1 (Torin1), a focused medicinal chemistry effort led to the discovery of an improved mTOR inhibitor 3 (Torin2), which possesses an EC[subscript 50] of 0.25 nM for inhibiting cellular mTOR activity. Compound 3 exhibited 800-fold selectivity over PI3K (EC[subscript 50]: 200 nM) and over 100-fold binding selectivity relative to 440 other protein kinases. Compound 3 has significantly improved bioavailability (54%), metabolic stability, and plasma exposure relative to compound 1. National Institutes of Health (U.S.) (Grant GM079575-03) 2012-11-01T17:44:56Z 2012-11-01T17:44:56Z 2011-02 2010-11 Article http://purl.org/eprint/type/JournalArticle 0022-2623 1520-4804 http://hdl.handle.net/1721.1/74550 Liu, Qingsong et al. “Discovery of 9-(6-aminopyridin-3-yl)-1-(3- (trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective and orally available mTOR inhibitor for treatment of cancer.” Journal of Medicinal Chemistry 54.5 (2011): 1473–1480. https://orcid.org/0000-0002-1446-7256 en_US http://dx.doi.org/10.1021/jm101520v Journal of Medicinal Chemistry Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) PMC |
| spellingShingle | Liu, Qingsong Wang, Jinhua Kang, Seong A. Thoreen, Carson C. Hur, Wooyoung Ahmed, Tausif Gray, Nathanael S. Sabatini, David Discovery of 9-(6-aminopyridin-3-yl)-1-(3- (trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective and orally available mTOR inhibitor for treatment of cancer |
| title | Discovery of 9-(6-aminopyridin-3-yl)-1-(3- (trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective and orally available mTOR inhibitor for treatment of cancer |
| title_full | Discovery of 9-(6-aminopyridin-3-yl)-1-(3- (trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective and orally available mTOR inhibitor for treatment of cancer |
| title_fullStr | Discovery of 9-(6-aminopyridin-3-yl)-1-(3- (trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective and orally available mTOR inhibitor for treatment of cancer |
| title_full_unstemmed | Discovery of 9-(6-aminopyridin-3-yl)-1-(3- (trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective and orally available mTOR inhibitor for treatment of cancer |
| title_short | Discovery of 9-(6-aminopyridin-3-yl)-1-(3- (trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective and orally available mTOR inhibitor for treatment of cancer |
| title_sort | discovery of 9 6 aminopyridin 3 yl 1 3 trifluoromethyl phenyl benzo h 1 6 naphthyridin 2 1h one torin2 as a potent selective and orally available mtor inhibitor for treatment of cancer |
| url | http://hdl.handle.net/1721.1/74550 https://orcid.org/0000-0002-1446-7256 |
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