EVT-701 is a novel selective and safe mitochondrial complex 1 inhibitor with potent anti-tumor activity in models of
Raquel Luna Yolba1, Virgile Visentin1, Caroline Hervé1
1Evotec SE, Curie Campus, Toulouse, France.
Abstract:
Targeting the first protein complex of the mitochondrial electron transport chain (MC1) in cancer has become an attractive therapeutic approach in the recent years, given the metabolic vulnerabilities of cancer cells. The anticancer effect exerted by the pleiotropic drug metformin and the associated reduction in hypoxia-inducible factor 1α (HIF-1α) levels putatively mediated by MC1 inhibition led to the development of HIF-1α inhibitors, such as BAY87-2243, with a more specific MC1 targeting. However, the development of BAY87-2243 was stopped early in phase 1 due to dose-independent emesis and thus there is still no clinical proof of concept for the approach. Given the importance of mitochondrial metabolism during cancer progression, there is still a strong therapeutic need to develop specific and safe MC1 inhibitors. We recently reported the synthesis of compounds with a novel chemotype and potent action on HIF-1α degradation and MC1 inhibition. We describe here the selectivity, safety profile and anti-cancer activity in solid tumors of lead compound EVT-701. In addition, using murine models of lung cancer and of Non-Hodgkin's B cell lymphoma we demonstrated that EVT-701 reduced tumor growth and lymph node invasion when used as a single agent therapy. LKB1 deficiency in lung cancer was identified as a potential indicator of accrued sensitivity to EVT-701, allowing stratification and selection of patients in clinical trials. Altogether these results support further evaluation of EVT-701 alone or in combination in preclinical models and eventually in patients.
Insights
A novel compound, EVT-701, effectively inhibits mitochondrial complex 1 (MC1) and reduces tumor growth in preclinical cancer models. LKB1 deficiency may predict patient response to this promising anti-cancer therapy.
Area of Science:
- Mitochondrial metabolism in cancer
- Cancer therapeutics
- Drug discovery and development
Background:
- Targeting mitochondrial complex 1 (MC1) is a promising cancer therapy strategy due to cancer cell metabolic vulnerabilities.
- Previous inhibitors like BAY87-2243 faced development hurdles, highlighting the need for safer, effective MC1 inhibitors.
- Metformin's effects on hypoxia-inducible factor 1α (HIF-1α) suggest MC1 as a key target.
Purpose of the Study:
- To evaluate the selectivity, safety, and anti-cancer activity of a novel MC1 inhibitor, EVT-701.
- To assess EVT-701's efficacy in preclinical models of solid tumors, specifically lung cancer and Non-Hodgkin's B cell lymphoma.
- To identify potential biomarkers for patient stratification in clinical trials.
Main Methods:
- Synthesis and characterization of novel chemotype compounds targeting MC1 and HIF-1α.
- In vitro assessment of compound selectivity and safety profile.
- In vivo studies using murine models of lung cancer and Non-Hodgkin's B cell lymphoma to evaluate anti-tumor effects.
Main Results:
- EVT-701 demonstrated potent MC1 inhibition and HIF-1α degradation.
- EVT-701 significantly reduced tumor growth and lymph node invasion in preclinical models.
- LKB1 deficiency was identified as a potential predictive biomarker for EVT-701 sensitivity in lung cancer.
Conclusions:
- EVT-701 exhibits promising anti-cancer activity and a favorable safety profile in preclinical studies.
- The compound warrants further investigation as a potential therapeutic agent for solid tumors, alone or in combination therapies.
- LKB1 deficiency offers a potential strategy for patient selection in future clinical trials.
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