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Identification of the Highly Active, Species Cross-Reactive Complex I Inhibitor BAY-179
Jeffrey Mowat1, Alexander H M Ehrmann2, Sven Christian1
1Pharmaceuticals R&D, Bayer AG, 13342 Berlin, Germany.
Abstract:
Mitochondria are key regulators of energy supply and cell death. Generation of ATP within mitochondria occurs through oxidative phosphorylation (OXPHOS), a process which utilizes the four complexes (complex I-IV) of the electron transport chain and ATP synthase. Certain oncogenic mutations (e.g., LKB1 or mIDH) can further enhance the reliance of cancer cells on OXPHOS for their energetic requirements, rendering cells sensitive to complex I inhibition and highlighting the potential value of complex I as a therapeutic target. Herein, we describe the discovery of a potent, selective, and species cross-reactive complex I inhibitor. A high-throughput screen of the Bayer compound library followed by hit triaging and initial hit-to-lead activities led to a lead structure which was further optimized in a comprehensive lead optimization campaign. Focusing on balancing potency and metabolic stability, this program resulted in the identification of BAY-179, an excellent in vivo suitable tool with which to probe the biological relevance of complex I inhibition in cancer indications.
Insights
Researchers discovered BAY-179, a potent inhibitor targeting mitochondrial complex I. This compound is a valuable tool for exploring complex I inhibition as a cancer therapy, especially in cancers relying heavily on oxidative phosphorylation (OXPHOS).
Area of Science:
- Mitochondrial biology and bioenergetics
- Cancer cell metabolism
- Drug discovery and medicinal chemistry
Background:
- Mitochondria are crucial for cellular energy (ATP) production via oxidative phosphorylation (OXPHOS) using electron transport chain complexes I-IV.
- Some cancers exhibit increased reliance on OXPHOS, making mitochondrial complex I a potential therapeutic target.
Purpose of the Study:
- To discover and develop a potent, selective, and cross-reactive inhibitor of mitochondrial complex I.
- To identify a suitable *in vivo* tool compound for investigating the therapeutic potential of complex I inhibition in cancer.
Main Methods:
- High-throughput screening of the Bayer compound library.
- Hit triaging, hit-to-lead optimization, and lead optimization campaign.
- Focus on optimizing potency and metabolic stability.
Main Results:
- Identification of BAY-179, a potent and selective inhibitor of mitochondrial complex I.
- BAY-179 demonstrates cross-species reactivity.
- The compound is suitable for *in vivo* studies.
Conclusions:
- BAY-179 is a well-characterized chemical probe for studying mitochondrial complex I function.
- This inhibitor provides a valuable tool for preclinical research into targeting OXPHOS in cancer.
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