2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase
Name
Vander Heiden_2-oxo.pdf
Size
624.3 KB
Format
Adobe PDF
Checksum (MD5)
e49550c5e960e7d2b36629b5ab73ff4b
Author(s)
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.
Date Issued
September 2011
Journal
Bioorganic & Medicinal Chemistry Letters
Publisher
Elsevier
Citation
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.
Version
Author's final manuscript
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-Noncommercial-NoDerivatives
Persistent DSpace Link
DOI of Published Version
http://dx.doi.org/10.1016/j.bmcl.2011.08.114
