Evaluation of substituted N,N'-diarylsulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase.
The metabolism of cancer cells is altered to support rapid proliferation. Pharmacological activators of a tumor cell specific pyruvate kinase isozyme (PKM2) may be an approach for altering the classic Warburg effect characteristic of aberrant metabolism in cancer cells yielding a novel antiproliferation strategy. In this manuscript, we detail the discovery of a series of substituted N,N'-diarylsulfonamides as activators of PKM2. The synthesis of numerous analogues and the evaluation of structure-activity relationships are presented as well as assessments of mechanism and selectivity. Several agents are found that have good potencies and appropriate solubility for use as chemical probes of PKM2 including 55 (AC(50) = 43 nM, maximum response = 84%; solubility = 7.3 microg/mL), 56 (AC(50) = 99 nM, maximum response = 84%; solubility = 5.7 microg/mL), and 58 (AC(50) = 38 nM, maximum response = 82%; solubility = 51.2 microg/mL). The small molecules described here represent first-in-class activators of PKM2.
Boxer
Matthew B
MB
NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, MSC 3370 Bethesda, Maryland 20850, USA.
Jiang
Jian-kang
JK
Vander Heiden
Matthew G
MG
Shen
Min
M
Skoumbourdis
Amanda P
AP
Southall
Noel
N
Veith
Henrike
H
Leister
William
W
Austin
Christopher P
CP
Park
Hee Won
HW
Inglese
James
J
Cantley
Lewis C
LC
Auld
Douglas S
DS
Thomas
Craig J
CJ
D001665:Binding Sites; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D015394:Molecular Structure; D011770:Pyruvate Kinase / Q000378:metabolism*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D013449:Sulfonamides; D007770:L-Lactate Dehydrogenase; D008156:Luciferases; D011770:Pyruvate Kinase