Dynamix Pharmaceuticals

Rehovot, Israel

Dynamix Pharmaceuticals

Rehovot, Israel
SEARCH FILTERS
Time filter
Source Type

Yacovan A.,Dynamix Pharmaceuticals | Ozeri R.,Dynamix Pharmaceuticals | Kehat T.,Dynamix Pharmaceuticals | Mirilashvili S.,Dynamix Pharmaceuticals | And 9 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

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. © 2012 Elsevier Ltd. All rights reserved.


PubMed | Dynamix Pharmaceuticals
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

10530 Background: Cancer cells undergo major metabolic changes to enable efficient conversion of glucose needed for cell growth and proliferation. This phenomenon, which takes place even when oxygen is abundant, is known as the Warburg effect. A key mediator of this effect is pyruvate kinase (PK), a rate-limiting enzyme that catalyzes the last step in glycolysis. PK subtype M2 (PKM2), which is over expressed in cancer cells, facilitates the Warburg effect by switching from a highly active tetrameric form to low activity monomeric or dimeric forms. Thus small molecule PKM2 activators that stabilize the tetrameric form are expected to renormalize cancer metabolism, offering a novel therapeutic strategy.Novel PKM2 activators were discovered using a structure-based approach, and tested in multiple in vitro and in vivo studies.Several series of novel, potent, allosteric PKM2 activators with AC50s as low as 20nM were discovered. By stabilizing the active tetrameric form of PKM2 more than 10-fold, these activators lower the levels of lactate in cancer cells, thus countering the Warburg effect. In cellular assays, these compounds significantly reduce the proliferation rate of multiple cancer cell lines, representing 5 different tumor types (colorectal, renal, lung, cervix, liver). So far, the greatest sensitivity was observed in colorectal cancer (CRC) and renal cell carcinoma (RCC) cell lines. Combination with commonly used chemotherapeutic agents show an additive, and in some cases a slight synergistic, effect on cells. In in vivo mouse xenograft models with the CRC cell line HT29, even a modestly active compound, such as DNX-03013 (AC50=0.9uM), demonstrated within a few days of treatment tumor growth inhibition greater than 50% (200 and 400 mg/kg IP QD). The compound was safe in mouse even at high exposure levels (400 mg/kg IP QD), indicating that these efficacious doses are significantly below the MTD.Taken together, this is the first report of potent PKM2 novel small-molecule cancer metabolism modulators that show promising anti-cancer therapeutic potential in vivo. The favorable DMPK profile of these compounds suggests that they can be further developed either as mono-therapy or as combination therapy.


PubMed | Dynamix Pharmaceuticals
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2012

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.

Loading Dynamix Pharmaceuticals collaborators
Loading Dynamix Pharmaceuticals collaborators