Complex I ROS Modulator

Target protein: 
CI ROS mod

Information

Call for collaboration proposals

We share an unprecedented, potent and selective NADH:ubiquinone oxidoreductase (Complex I) ROS modulator for collaborative research on novel disease indications. This tool compound lowers oxidative stress by inhibiting the generation of reactive oxygen species (ROS), derived from mitochondrial Complex I, while leaving the NADH:ubiquinone oxidoreductase activity unaffected. The Complex I ROS modulator is brain penetrant and shows pharmacokinetic (PK) properties that are suitable for in vivo testing in in several animal species. The compound will be provided free of charge in the amount required for the experiments.

Funding of up to 200.000 Euro will be available upon request and shall be outlined in the submission proposal. Collaborating scientists will benefit from direct access to Boehringer Ingelheim’s drug discovery and validation capabilities.

Additional compounds having differentiated properties and pharmacological profiles may also be available for sharing on request. We invite scientists to submit proposals containing a testable hypothesis using our Complex I ROS modulator no later than September 15, 2018 23.59 pm PST.

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Target information

Due to its relative slow turnover rate for ubiquinone reduction NADH:ubiquinone oxidoreductase (Complex I) is the rate-limiting enzyme in the mitochondrial electron transfer chain (respiratory chain). Genetic and functional evidence indicates that Complex I is a major source of mitochondrial ROS-formation [1] and thus a major contributor to oxidative stress, a pathological hallmark in neurodegenerative and other diseases [2-5]. Hence, a Complex I ROS modulator which lowers ROS-production while leaving the ubiquinone reduction mechanism unaffected is expected to reduce oxidative stress in a more targeted (i.e. intra-mitochondrial) and more specific manner (i.e. non-stoichiometric scavenging) than other antioxidants that failed in clinical trials.

In-Vitro Activity

The novel Boehringer Ingelheim small molecule inhibits purified bovine Complex I mediated ROS-formation with an IC50 of 80 nM. Compounds from this series have been shown to have no species selectivity. The Complex I ROS modulator was also shown to be selective versus other ROS-generating enzymes (e.g. xanthine oxidase, monoamine oxidase and NO-synthases all >10µM) and does not show cytotoxicity at 30 µM in neuroblastoma cells, indicating that mitochondrial respiration is unaffected (modulation concept). Furthermore the small molecule protects glutathione-depleted neuroblastoma cells in a model of oxidative stress (HT22 cells, EC50 = 80 nM) and dopaminergic neurons in the MPTP-model, a neurotoxin inhibiting mitochondrial Complex I resulting in diminished ubiquinone-reduction and ATP synthesis as well as stimulated ROS-formation.

In vitro activity table

Assay IC50 [nM]
Complex I IC50 (bovine) 80
Xanthinoxidase IC50 (ROS generation) >10000
HT22 cell protection EC50 35

In-vitro DMPK parameters

The Boehringer Ingelheim Complex I ROS modulator has acceptable solubility in water at neutral pH and high permeability in Caco2 and MDCK assays.

In-vivo DMPK parameters

PK properties in several animal species are suitable for once or twice daily oral dosing in acute or sub-chronic in vivo experiments.

Selectivity

The small molecule shows high selectivity at 10 µM concentration versus a panel of 68 receptors (no inhibition), 25 Kinases (IKKβ and VEGFR2 >75% inhibition) and 17 other enzymes (15-LO, 5-LO and LPO >75% inhibition). Initial safety studies in rats showed no cardiovascular effects up to a 50 mg/kg dose.

Supplementary data

The front-runner Complex I ROS modulator is a member of a family of compounds generated in our Complex I modulator program. Additional compounds have different properties and pharmacological profiles and may be available for sharing.

Summary

We share an unprecedented, potent and selective Complex I ROS modulator for collaborative research on novel disease indications. This tool compound is brain penetrant and shows PK properties that are suitable for in vivo testing in several animal species. We invite scientists to submit proposals containing a testable hypothesis using our Complex I ROS modulator.

References

  1. How mitochondria produce reactive oxygen species.

    Murphy

    Biochem. J. 2009, 417(1), 1-13.

  2. Mitochondrial complex I: structure, function and pathology.

    Janssen et al.

    J. Inherit. Metab. Dis. 2006, 29(4), 499-515.

  3. Leber's Hereditary Optic Neuropathy-Gene Therapy: From Benchtop to Bedside.

    Koilkonda et al.

    J. Ophtalmol. 2011, 179412.

  4. Coexistence of mutations in PINK1 and mitochondrial DNA in early onset parkinsonism.

    Piccoli et al.

    J. Med. Genet. 2008, 45(9), e5508.

  5. Mitochondrial DNA Variants of Respiratory Complex I that Uniquely Characterize Haplogroup T2 Are Associated with Increased Risk of Age-Related Macular Degeneration

    SanGiovanni et al.

    PLoS One. 2009, 4(5), 197-201.