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 a...

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Autores principales:	Raquel Luna Yolba, Virgile Visentin, Caroline Hervé, Johanna Chiche, Jean‐Ehrland Ricci, Jérôme Méneyrol, Michaël R. Paillasse, Nathalie Alet
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	DLBCL LKB1 lung cancer mitochondrial complex 1 Non‐Hodgkin's lymphoma STK11 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/3d0f4b7296d44acb870aa7784d8f98ab
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spelling	oai:doaj.org-article:3d0f4b7296d44acb870aa7784d8f98ab2021-11-16T13:45:54ZEVT‐701 is a novel selective and safe mitochondrial complex 1 inhibitor with potent anti‐tumor activity in models of solid cancers2052-170710.1002/prp2.854https://doaj.org/article/3d0f4b7296d44acb870aa7784d8f98ab2021-10-01T00:00:00Zhttps://doi.org/10.1002/prp2.854https://doaj.org/toc/2052-1707Abstract 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.Raquel Luna YolbaVirgile VisentinCaroline HervéJohanna ChicheJean‐Ehrland RicciJérôme MéneyrolMichaël R. PaillasseNathalie AletWileyarticleDLBCLLKB1lung cancermitochondrial complex 1Non‐Hodgkin's lymphomaSTK11Therapeutics. PharmacologyRM1-950ENPharmacology Research & Perspectives, Vol 9, Iss 5, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	DLBCL LKB1 lung cancer mitochondrial complex 1 Non‐Hodgkin's lymphoma STK11 Therapeutics. Pharmacology RM1-950
spellingShingle	DLBCL LKB1 lung cancer mitochondrial complex 1 Non‐Hodgkin's lymphoma STK11 Therapeutics. Pharmacology RM1-950 Raquel Luna Yolba Virgile Visentin Caroline Hervé Johanna Chiche Jean‐Ehrland Ricci Jérôme Méneyrol Michaël R. Paillasse Nathalie Alet EVT‐701 is a novel selective and safe mitochondrial complex 1 inhibitor with potent anti‐tumor activity in models of solid cancers
description	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.
format	article
author	Raquel Luna Yolba Virgile Visentin Caroline Hervé Johanna Chiche Jean‐Ehrland Ricci Jérôme Méneyrol Michaël R. Paillasse Nathalie Alet
author_facet	Raquel Luna Yolba Virgile Visentin Caroline Hervé Johanna Chiche Jean‐Ehrland Ricci Jérôme Méneyrol Michaël R. Paillasse Nathalie Alet
author_sort	Raquel Luna Yolba
title	EVT‐701 is a novel selective and safe mitochondrial complex 1 inhibitor with potent anti‐tumor activity in models of solid cancers
title_short	EVT‐701 is a novel selective and safe mitochondrial complex 1 inhibitor with potent anti‐tumor activity in models of solid cancers
title_full	EVT‐701 is a novel selective and safe mitochondrial complex 1 inhibitor with potent anti‐tumor activity in models of solid cancers
title_fullStr	EVT‐701 is a novel selective and safe mitochondrial complex 1 inhibitor with potent anti‐tumor activity in models of solid cancers
title_full_unstemmed	EVT‐701 is a novel selective and safe mitochondrial complex 1 inhibitor with potent anti‐tumor activity in models of solid cancers
title_sort	evt‐701 is a novel selective and safe mitochondrial complex 1 inhibitor with potent anti‐tumor activity in models of solid cancers
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/3d0f4b7296d44acb870aa7784d8f98ab
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EVT‐701 is a novel selective and safe mitochondrial complex 1 inhibitor with potent anti‐tumor activity in models of solid cancers

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