1-(sulfonyl)-5-(arylsulfonyl)indoline as activators of the tumor cell specific M2 isoform of pyruvate kinase
| Autor: | Alex Aizikovich, Alexander Konson, Nili Schutz, Alina Shitrit, Avihai Yacovan, Sima Mirilashvili, Rachel Ozeri, Daniel Sherman, Osnat Bohana-Kashtan, Oren M. Becker, Tzofit Kehat, Vered Behar, Efrat Ben-Zeev |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Thyroid Hormones
Indoles Pyruvate Kinase Clinical Biochemistry Pharmaceutical Science PKM2 Biochemistry Neoplasms Drug Discovery Humans Protein Isoforms Glycolysis Molecular Biology chemistry.chemical_classification biology Chemistry Organic Chemistry Membrane Proteins Active site Sulfinic Acids Warburg effect Small molecule Neoplasm Proteins Enzyme Activation Molecular Docking Simulation Enzyme Cancer cell biology.protein Molecular Medicine Caco-2 Cells Protein Multimerization Carrier Proteins Pyruvate kinase |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 22:6460-6468 |
| ISSN: | 0960-894X |
| Popis: | Cancer cells preferentially use glycolysis rather than oxidative phosphorylation for their rapid growth. They consume large amount of glucose to produce lactate even when oxygen is abundant, a phenomenon known as the Warburg effect. This metabolic change originates from a shift in the expression of alternative spliced isoforms of the glycolytic enzyme pyruvate kinase (PK), from PKM1 to PKM2. While PKM1 is constitutively active, PKM2 is switched from an inactive dimer form to an active tetramer form by small molecule activators. The prevalence of PKM2 in cancer cells relative to the prevalence of PKM1 in many normal cells, suggests a therapeutic strategy whereby activation of PKM2 may counter the abnormal cellular metabolism in cancer cells, and consequently decreased cellular proliferation. Herein we describe the discovery and optimization of a series of PKM2 activators derived from the 2-((2,3-dihydrobenzo[b][1,4] dioxin-6-yl)thio)-1-(2-methyl-1-(methylsulfonyl)indolin-5-yl) ethanone scaffold. The synthesis, SAR analysis, enzyme active site docking, enzymatic reaction kinetics, selectivity and pharmaceutical properties are discussed. |
| Databáze: | OpenAIRE |
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