title: 1-(sulfonyl)-5-(arylsulfonyl)indoline as activators of the tumor cell specific M2 isoform of pyruvate kinase.
abstract: 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.
authors.affiliation: Dynamix Pharmaceuticals, Rehovot 76385, Israel. ayacovan@dynxp.com
authors.forename: Avihai
authors.initials: A
authors.lastname: Yacovan
authors.forename: Rachel
authors.initials: R
authors.lastname: Ozeri
authors.forename: Tzofit
authors.initials: T
authors.lastname: Kehat
authors.forename: Sima
authors.initials: S
authors.lastname: Mirilashvili
authors.forename: Daniel
authors.initials: D
authors.lastname: Sherman
authors.forename: Alex
authors.initials: A
authors.lastname: Aizikovich
authors.forename: Alina
authors.initials: A
authors.lastname: Shitrit
authors.forename: Efrat
authors.initials: E
authors.lastname: Ben-Zeev
authors.forename: Nili
authors.initials: N
authors.lastname: Schutz
authors.forename: Osnat
authors.initials: O
authors.lastname: Bohana-Kashtan
authors.forename: Alexander
authors.initials: A
authors.lastname: Konson
authors.forename: Vered
authors.initials: V
authors.lastname: Behar
authors.forename: Oren M
authors.initials: OM
authors.lastname: Becker
mesh_terms: D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000819:agonists* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D008565:Membrane Proteins / Q000819:agonists* / Q000378:metabolism; D062105:Molecular Docking Simulation; D009363:Neoplasm Proteins / Q000819:agonists* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D011770:Pyruvate Kinase / Q000378:metabolism; D013441:Sulfinic Acids / Q000737:chemistry / Q000494:pharmacology; D013963:Thyroid Hormones / Q000819:agonists* / Q000378:metabolism; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D007211:Indoles; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D011770:Pyruvate Kinase; D013441:Sulfinic Acids; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins