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Overview

Tags

Neoplasms

Immune System Diseases

Endocrinology and Metabolic Disease

Small molecule drug

Disease domain score

A glimpse into the focused therapeutic areas

Technology Platform

Most used technologies in drug development

Targets

Most frequently developed targets

Disease Domain	Count

Neoplasms	4
Immune System Diseases	2
Endocrinology and Metabolic Disease	1
Hemic and Lymphatic Diseases	1

Top 5 Drug Type	Count

Small molecule drug	6

Top 5 Target	Count

JAK3(Tyrosine-protein kinase JAK3)	1
FAK x PYK2	1
PKM2(Pyruvate kinase isozymes M1/M2)	1
PLK1(Polo like kinase 1)	1
Syk(Spleen tyrosine kinase)	1

AbstractPyruvate kinase (PK) M2 which catalyzes the last step in glycolysis, is the alternative spliced isoform expressed in cancer cells, and a key player in exerting the Warburg effect. One of the mechanisms by which PKM2 modulate cancer cell metabolism is by switching between the low activity monomer and the high activity tetramer forms. This process is controlled by the varying concentration of an upstream glycolytic intermediate, FBP. These changes enable the cancer cell to manage its usage of glucose carbon backbones, whether for ATP production or for biomass generation, according to its changing demands. Further, it has been recently shown that the elevated levels of ROS in cancer cells contribute to the decreased activity of PKM2 to support NADPH production to increase cellular anti-oxidation capacity to sustain proliferation. Our goal is to disrupt the metabolic adaptation of cancer cells with small molecule PKM2 modulators. We hypothesized that an activator will redirect the consumption of nutrients, especially of glucose, away from biomass production and ultimately send the cells to die. Using our proprietary structure-based technology, we identified several series of novel allosteric PKM2 activators. Chemical optimization resulted in potent compounds with AC50 as low as 10nM, which were selective against the other PK isoforms. These compounds were proven to stabilize the active tetramer form of PKM2 in cancer cells. Bioenergetic experiments in several cell lines demonstrated that not only do these agents reduce lactate production; they also reduce the oxygen consumption rate. Analysis of cell cycle showed that treatment with PKM2 activators causes the cells to arrest at the G1 phase. In outcome-based assays, these compounds significantly reduced the proliferation rate of various cancer cell lines, and this effect was sensitive to media conditions, such as glucose levels. Taken together, our data supports the hypothesis that activation of PKM2 effectively deprives the cancer cell of building blocks and reduces the detoxification capacity that are required to support growth and proliferation. An in vivo colorectal cancer HT29 cell line mouse xenograft model with a modestly active compound (IC50=0.9uM) demonstrated tumor growth inhibition greater than 50% (100 mg/kg Q2D and 200 and 400 mg/kg IP QD). The compound was very safe in mouse, even at the highest exposure levels (200 and 400 mg/kg IP QD), indicating that these efficacious doses are significantly lower than the MTD. Additional xenograft models are ongoing. Taken together, there is strong support for the effect of potent PKM2 small molecule activators on the cellular metabolism of cancer cells, demonstrating statistically significant anti-cancer effect in an animal model of colorectal cancer. The favorable DMPK profile of these compounds further supports their development as anti-proliferative agents, both as a single agent and in combination therapy.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3219. doi:1538-7445.AM2012-3219

15 Apr 2011·Cancer Research

Abstract 4065: Modulation of cancer metabolism with novel PKM2 activators exerts anti-tumor activity

Author: Sherman, Daniel ; Bohana-Kashtan, Osnat ; Schutz, Nili C. ; Shitrit, Alina ; Becker, Oren M. ; Yakovan, Avihai ; Behar, Vered

AbstractCancer cells adapt altered metabolism to enable efficient conversion of glucose into biomass needed for massive cell growth and proliferation. The metabolic switch takes place even when oxygen is abundant, a phenomenon known as the Warburg effect. A key mediator of this effect is pyruvate kinase type M2 (PKM2), a rate-limiting enzyme, which catalyzes the last step in glycolysis, converting PEP and ADP to pyruvate and ATP. PKM2 switches between a highly active tetrameric form and low activity monomeric or dimeric forms, following binding to its natural allosteric activator FBP (an upstream glycolytic intermediate). Our goal was to identify novel small molecule PKM2 activators that can be used as potential anti-cancer therapeutics.Using our proprietary structure-based screening tools, we identified several novel, potent, allosteric PKM2 activators, with AC50s as low as 50nM and 150% activation levels, similar to the natural activator FBP (AC50=116nM, 150% activation). Kinetics studies showed that these compounds significantly improve the rate and efficiency of the enzymatic reaction to the same level as FBP (a 4-fold decrease in KM, and a 2-fold increase in VMAX). Furthermore, a greater increase in VMAX (3-fold) is observed when combining these compounds with FBP. These small-molecule activators induce the formation of the (active) tetrameric form of PKM2, increasing the PKM2 tetramer:monomer ratio by more than 10-fold, quantitatively similar to the action of FBP. In cellular assays, these compounds show significant reduction in the proliferation rate of cancer cell lines, including colorectal, lung and hepatic carcinomas, in a dose- and time-dependent manner (up to 80% proliferation inhibition). In line with the ability of these novel compounds to re-direct cellular metabolism from aerobic glycolysis to oxidative phosphorylation, we found that inhibition of oxidative phosphorylation with oligomycin extends the anti proliferative effect of our compounds. When used in combination with commonly used chemotherapeutic agents, such as 5FU in colorectal cancer cells, they show an additive effect and yielded close to 100% inhibition of cell growth. Our compounds demonstrate excellent in vitro and in vivo DMPK profiles, including metabolic stability, excellent permeability with no efflux (CaCO-2 PApp=20.5 106/cm·s-1), and in vivo mouse pharmacokinetics with 20% oral bioavailability, good half life PO and volume of distribution. Several animal efficacy studies, as mono-therapy and in combination with chemotherapy or specific kinase inhibitors, are ongoing.Taken together, we present a new class of potent PKM2 activators that modulate the metabolism within cancer cells and show a promising anti cancer therapeutics potential. The favorable DMPK profile of these compounds suggests that they can be further developed either as mono-therapy or in combination with targeted therapeutics or chemo-therapy.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4065. doi:10.1158/1538-7445.AM2011-4065

100 Deals associated with Dynamix Pharmaceuticals Ltd.

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100 Translational Medicine associated with Dynamix Pharmaceuticals Ltd.

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Pipeline

Pipeline Snapshot as of 19 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

Discovery

3

Preclinical

Other

2

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

DNX-3000 ( PKM2 )	Neoplasms More	Preclinical
DNX-4000 ( JAK3 )	Autoimmune Diseases More	Preclinical
DNX-5000 ( FAK x PYK2 )	Osteoporosis More	Preclinical
DNX-6000	Neoplasms More	Discovery
DNX-1000 ( PLK1 )	Neoplasms More	Discovery