EVT‐701 is a novel selective and safe mitochondrial complex 1 inhibitor with potent anti‐tumor activity in models of solid cancers

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.

Residual Complex I activity supports glutamate catabolism and mtSLP via canonical Krebs cycle activity during acute anoxia without OXPHOS

“…Relevant to the results published in (Martinez-Reyes et al ., 2020), the role of CI in the proliferation of cancer cells has been reviewed in (Urra et al, 2017), and the consensus was that a complete- as opposed to an incomplete- loss of CI activity halts tumor growth, although avoidance of ROS generation was proposed to mediate this effect. In addition, the CI inhibitor EVT-701 exhibiting potency against solid cancers in murine models and human cell lines is in line for being evaluated in clinical trials (Luna Yolba et al, 2021).…”

“…Relevant to the results published in (Martinez-Reyes et al ., 2020), the role of CI in the proliferation of cancer cells has been reviewed in (Urra et al, 2017), and the consensus was that a complete- as opposed to an incomplete- loss of CI activity halts tumor growth, although avoidance of ROS generation was proposed to mediate this effect. In addition, the CI inhibitor EVT-701 exhibiting potency against solid cancers in murine models and human cell lines is in line for being evaluated in clinical trials (Luna Yolba et al, 2021). CI has been described to exist in two forms, an active (A) and a de-active (D) form, the latter signifying a dormant state of the complex which is not inactivated or covalently modified in any way (Babot et al, 2014); the A to D transition occurs during ischemia, i.e .…”

Impact of Opioids on Cellular Metabolism: Implications for Metabolic Pathways Involved in Cancer

“…The association between poor clinical outcome and downregulation of OXPHOS enzymes is attributed to the correlated increase in EMT. Targeting complexes I–IV of the ETC was shown to successfully reduce tumor growth and induce apoptosis [ 191 , 192 , 193 ]. Overall regulation of OXPHOS unsurprisingly varies in different cancer types and can even be heterogenous within tumors [ 194 , 195 , 196 ].…”

Selective Mitochondrial Respiratory Complex I Subunit Deficiency Causes Tumor Immunogenicity

“…Due to the prominent role of OxPhos and mitochondria in tumor growth and metastasis, significant efforts have been made to create OxPhos inhibitors, especially against CI, the NADH dehydrogenase complex. CI inhibitors have been very promising in the preclinical stage at treating a variety of cancer types [15][16][17][18] . However, once translated to the clinic, all inhibitors tested in humans have failed phase I clinical trials due to dose-limiting toxicities 19,20 .…”