2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase
Compared to normal differentiated cells, cancer cells have altered metabolic regulation to support biosynthesis and the expression of the M2 isozyme of pyruvate kinase (PKM2) plays an important role in this anabolic metabolism. While the M1 isoform is a highly active enzyme, the alternatively splice...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2015
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| Online Access: | http://hdl.handle.net/1721.1/99178 https://orcid.org/0000-0002-6702-4192 |
| _version_ | 1811075185679269888 |
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| author | Walsh, Martin J. Brimacombe, Kyle R. Veith, Henrike Bougie, James M. Daniel, Thomas Leister, William Cantley, Lewis C. Vander Heiden, Matthew G. Shen, Min Auld, Douglas S. Thomas, Craig J. Boxer, Matthew B. Israelsen, William James |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Walsh, Martin J. Brimacombe, Kyle R. Veith, Henrike Bougie, James M. Daniel, Thomas Leister, William Cantley, Lewis C. Vander Heiden, Matthew G. Shen, Min Auld, Douglas S. Thomas, Craig J. Boxer, Matthew B. Israelsen, William James |
| author_sort | Walsh, Martin J. |
| collection | MIT |
| description | Compared to normal differentiated cells, cancer cells have altered metabolic regulation to support biosynthesis and the expression of the M2 isozyme of pyruvate kinase (PKM2) plays an important role in this anabolic metabolism. While the M1 isoform is a highly active enzyme, the alternatively spliced M2 variant is considerably less active and expressed in tumors. While the exact mechanism by which decreased pyruvate kinase activity contributes to anabolic metabolism remains unclear, it is hypothesized that activation of PKM2 to levels seen with PKM1 may promote a metabolic program that is not conducive to cell proliferation. Here we report the third chemotype in a series of PKM2 activators based on the 2-oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamide scaffold. The synthesis, structure activity relationships, selectivity and notable physiochemical properties are described. |
| first_indexed | 2024-09-23T10:02:11Z |
| format | Article |
| id | mit-1721.1/99178 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:02:11Z |
| publishDate | 2015 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/991782022-09-30T18:26:31Z 2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase Walsh, Martin J. Brimacombe, Kyle R. Veith, Henrike Bougie, James M. Daniel, Thomas Leister, William Cantley, Lewis C. Vander Heiden, Matthew G. Shen, Min Auld, Douglas S. Thomas, Craig J. Boxer, Matthew B. Israelsen, William James Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Israelsen, William J. Vander Heiden, Matthew G. Compared to normal differentiated cells, cancer cells have altered metabolic regulation to support biosynthesis and the expression of the M2 isozyme of pyruvate kinase (PKM2) plays an important role in this anabolic metabolism. While the M1 isoform is a highly active enzyme, the alternatively spliced M2 variant is considerably less active and expressed in tumors. While the exact mechanism by which decreased pyruvate kinase activity contributes to anabolic metabolism remains unclear, it is hypothesized that activation of PKM2 to levels seen with PKM1 may promote a metabolic program that is not conducive to cell proliferation. Here we report the third chemotype in a series of PKM2 activators based on the 2-oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamide scaffold. The synthesis, structure activity relationships, selectivity and notable physiochemical properties are described. National Human Genome Research Institute (U.S.) (Molecular Libraries Initiative of the NIH Roadmap for Medical Research) 2015-10-07T15:04:46Z 2015-10-07T15:04:46Z 2011-09 2011-08 Article http://purl.org/eprint/type/JournalArticle 0960894X http://hdl.handle.net/1721.1/99178 Walsh, Martin J., Kyle R. Brimacombe, Henrike Veith, James M. Bougie, Thomas Daniel, William Leister, Lewis C. Cantley, et al. “2-Oxo-N-Aryl-1,2,3,4-Tetrahydroquinoline-6-Sulfonamides as Activators of the Tumor Cell Specific M2 Isoform of Pyruvate Kinase.” Bioorganic & Medicinal Chemistry Letters 21, no. 21 (November 2011): 6322–6327. https://orcid.org/0000-0002-6702-4192 en_US http://dx.doi.org/10.1016/j.bmcl.2011.08.114 Bioorganic & Medicinal Chemistry Letters Creative Commons Attribution-Noncommercial-NoDerivatives http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Walsh, Martin J. Brimacombe, Kyle R. Veith, Henrike Bougie, James M. Daniel, Thomas Leister, William Cantley, Lewis C. Vander Heiden, Matthew G. Shen, Min Auld, Douglas S. Thomas, Craig J. Boxer, Matthew B. Israelsen, William James 2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase |
| title | 2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase |
| title_full | 2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase |
| title_fullStr | 2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase |
| title_full_unstemmed | 2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase |
| title_short | 2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase |
| title_sort | 2 oxo n aryl 1 2 3 4 tetrahydroquinoline 6 sulfonamides as activators of the tumor cell specific m2 isoform of pyruvate kinase |
| url | http://hdl.handle.net/1721.1/99178 https://orcid.org/0000-0002-6702-4192 |
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