Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase.
Cancer cells have distinct metabolic needs that are different from normal cells and can be exploited for development of anti-cancer therapeutics. Activation of the tumor specific M2 form of pyruvate kinase (PKM2) is a potential strategy for returning cancer cells to a metabolic state characteristic of normal cells. Here, we describe activators of PKM2 based upon a substituted thieno[3,2-b]pyrrole[3,2-d]pyridazinone scaffold. The synthesis of these agents, structure-activity relationships, analysis of activity at related targets (PKM1, PKR and PKL) and examination of aqueous solubility are investigated. These agents represent the second reported chemotype for activation of PKM2.
Jiang
Jian-kang
JK
NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
Boxer
Matthew B
MB
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
D020536:Enzyme Activators / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology*; D011770:Pyruvate Kinase / Q000378:metabolism*; D013329:Structure-Activity Relationship
D020536:Enzyme Activators; D007527:Isoenzymes; D011724:Pyridazines; D011770:Pyruvate Kinase
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