1-(sulfonyl)-5-(arylsulfonyl)indoline as activators of the tumor cell specific M2 isoform of pyruvate kinase

Yacovan, Avihai; Ozeri, Rachel; Kehat, Tzofit; Mirilashvili, Sima; Sherman, Daniel; Aizikovich, Alex; Shitrit, Alina; Ben-Zeev, Efrat; Schutz, Nili; Bohana‐Kashtan, Osnat; Konson, Alexander; Behar, Vered; Becker, Oren M.

doi:10.1016/j.bmcl.2012.08.054

Cited by 36 publications

(22 citation statements)

References 16 publications

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“…The mechanism underlying this activation remains to be defined. A series of PKM2 activators (1-(sulfonyl)-5-(arylsulfonyl)indoline) were also reported very recently [86]. In contrast to these, potent small molecule PKM2 inhibitors which may in part induce cell death by inhibiting PKM2 activity have also been developed [87].…”

Section: Regulation Of Pkm2 In the Warburg Effect During Tumorigenmentioning

confidence: 99%

PKM2, a Central Point of Regulation in Cancer Metabolism

Wong

Melo

Tang

2013

International Journal of Cell Biology

198

165

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Aerobic glycolysis is the dominant metabolic pathway utilized by cancer cells, owing to its ability to divert glucose metabolites from ATP production towards the synthesis of cellular building blocks (nucleotides, amino acids, and lipids) to meet the demands of proliferation. The M2 isoform of pyruvate kinase (PKM2) catalyzes the final and also a rate-limiting reaction in the glycolytic pathway. In the PK family, PKM2 is subjected to a complex regulation by both oncogenes and tumour suppressors, which allows for a fine-tone regulation of PKM2 activity. The less active form of PKM2 drives glucose through the route of aerobic glycolysis, while active PKM2 directs glucose towards oxidative metabolism. Additionally, PKM2 possesses protein tyrosine kinase activity and plays a role in modulating gene expression and thereby contributing to tumorigenesis. We will discuss our current understanding of PKM2's regulation and its many contributions to tumorigenesis.

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Section: Regulation Of Pkm2 In the Warburg Effect During Tumorigenmentioning

confidence: 99%

PKM2, a Central Point of Regulation in Cancer Metabolism

Wong

Melo

Tang

2013

International Journal of Cell Biology

198

165

View full text Add to dashboard Cite

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“…3-Pyrrole derivatives (35, AC 50 = 4.34 µM) exhibited higher activity than 2-pyrrole derivatives (27, AC 50 > 20 µM), which further demonstrated that the position of substituent was crucial for the activity. Furthermore, replacing the benzene ring in compound 8 with naphthalene ring (23 and 24), or introducing multiple substituents (20,21,22) led to the decrease or completely lost of activity, which indicated that larger steric hindrance was unfavorable to the activity.…”

Section: Biological Evaluations In Vitromentioning

confidence: 98%

“…1) have been reported including a series of N,N'-diarylsulfonamides (1), 17 thieno [3,2-b]pyrrole [3,2-d]pyridazinones (2), 18 2-oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides (3), 19 quinolone sulfonamides (4), 20 1-(sulfonyl)-5-(arylsulfonyl)indoline (5), 21 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones (6) 22 and 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (7). 23 Even though, the above compounds have no antiproliferative effects on tumor cell lines except that serine was deprived from the medium.…”

Section: Introductionmentioning

confidence: 99%

New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds

Zhang

Liu

et al. 2015

Bioorganic & Medicinal Chemistry

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“…Also this activator binds the enzyme at the interface of the two monomers of the protein and makes a strong p-p stacking interaction with the two Phe26 residues of the protein. 52 Lactate dehydrogenase (LDH): One of the most attractive glycolytic targets is the enzyme lactate dehydrogenase (LDH), which catalyzes the reversible conversion of pyruvate to lactate with the simultaneous oxidation of the cofactor NADH to NAD + . The human isoform LDH-A or LDH5 is composed of four A subunits (LDH-A 4 ) and is mainly expressed in liver and muscle.…”

Section: Introductionmentioning

confidence: 99%

An update on therapeutic opportunities offered by cancer glycolytic metabolism

Granchi

Fancelli

Minutolo

2014

Bioorganic & Medicinal Chemistry Letters

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Almost all invasive cancers, regardless of tissue origin, are characterized by specific modifications of their cellular energy metabolism. In fact, a strong predominance of aerobic glycolysis over oxidative phosphorylation (Warburg effect) is usually associated with aggressive tumour phenotypes. This metabolic shift offers a survival advantage to cancer cells, since they may continue to produce energy and anabolites even when they are exposed to either transient or permanent hypoxic conditions. Moreover, it ensures a high production rate of glycolysis intermediates, useful as building blocks for fast cell proliferation of cancer cells. This peculiar metabolic profile may constitute an ideal target for therapeutic interventions that selectively hit cancer cells with minimal residual systemic toxicity. In this review we provide an update about some of the most recent advances in the discovery of new bioactive molecules that are able to interfere with cancer glycolysis.

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1-(sulfonyl)-5-(arylsulfonyl)indoline as activators of the tumor cell specific M2 isoform of pyruvate kinase

Cited by 36 publications

References 16 publications

PKM2, a Central Point of Regulation in Cancer Metabolism

PKM2, a Central Point of Regulation in Cancer Metabolism

New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds

An update on therapeutic opportunities offered by cancer glycolytic metabolism

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