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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)6460-6468
Number of pages9
JournalBioorganic and Medicinal Chemistry Letters
Issue number20
StatePublished - 15 Oct 2012
Externally publishedYes


  • Anti-cancer strategies
  • Cellular metabolism
  • PKM2
  • Pyruvate kinase
  • Small molecule activators


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