Small Molecule Metabolism Potentiators That Activate NRF2-Mediated Cytoprotective Transcriptional Programs

SUMMARY

• The KEAP1-NRF2 pathway is implicated in a wide range of diseases and as such, is a highly sought-after drug target. Problematically, past therapeutic approaches failed due to safety and toxicity of electrophilic NRF2 activators. 
• The inventors developed a novel strategy to indirectly activate NRF2 using a non-covalent metabolism modulating approach. This indirect activation approach can achieve the same therapeutic effects, while potentially alleviating safety and toxicity concerns of covalent inhibitors.
• The invention is a series of small molecules that induce the initiation of NRF2-mediated antioxidant and cytoprotective transcriptional programs. The molecules non-covalently inhibit upstream PGK1, which causes the accumulation of a glycolytic metabolite capable of upregulating NRF2 expression.
• In vivo mouse models of UV skin cancer were used to validate the small molecules, since this cancer was previously shown to be mediated by NRF2 signaling. The chemical scaffold of the small molecule (CBR-470-2) resulted in a decrease in cancer-associated inflammation markers when administered orally that was comparable to a clinical stage covalent KEAP1 agonist, bardoxolone methyl (BARD).  

FIGURE

BALB/C male mice were hair removed and exposed to UVB at an area of 8cm2 and doses of 200mJ/cm2 were confirmed using dosimeter measurements. Mice were dosed twice daily (day 0-day 10) with BARD (3mg/mg orally) or the crude and un-optimized scaffold of the invention compound (50mg/mg orally). Percent wound area (A) and epidermal thickness (B) were quantified from the raw animal images (C).

ADVANTAGES

ADVANTAGES

• Novel metabolism modulating mechanism of action
• Expandable to multiple disease indications 
• Multiple novel lead compounds

APPLICATIONS

• Respiratory diseases
• Inflammation
• Aging
• Neurodegenerative diseases
• Cancers (NRF2 dependent)

PUBLICATIONS

• Bollong, MJ; et al. A metabolite-derived protein modification integrates glycolysis with KEAP1-NFR2 Signaling. Nature. 2018 Oct; 562(7728):600-604.

Jul 26, 2019

Licensing,Co-Development

Patent Pending

In vivo preclinical|Current data for melanoma and lung inflammation|Further indications under evaluation

Ray Moellering