Characterization of TR-107, a novel chemical activator of the human mitochondrial protease ClpP.

Animals Endopeptidase Clp / chemistry Humans Mice Mitochondria / metabolism Mitochondrial Proteins / metabolism Peptide Hydrolases / metabolism Triple Negative Breast Neoplasms / drug therapy
agonist cell proliferation mitochondria oxidative phosphorylation protease small molecule triple-negative breast cancer

Journal

Pharmacology research & perspectives
ISSN: 2052-1707
Titre abrégé: Pharmacol Res Perspect
Pays: United States
ID NLM: 101626369

Informations de publication

Date de publication:
08 2022
Historique:
received: 31 05 2022
accepted: 03 06 2022
entrez: 5 8 2022
pubmed: 6 8 2022
medline: 10 8 2022
Statut: ppublish

Résumé

We recently described the identification of a new class of small-molecule activators of the mitochondrial protease ClpP. These compounds synthesized by Madera Therapeutics showed increased potency of cancer growth inhibition over the related compound ONC201. In this study, we describe chemical optimization and characterization of the next generation of highly potent and selective small-molecule ClpP activators (TR compounds) and demonstrate their efficacy against breast cancer models in vitro and in vivo. We selected one compound (TR-107) with excellent potency, specificity, and drug-like properties for further evaluation. TR-107 showed ClpP-dependent growth inhibition in the low nanomolar range that was equipotent to paclitaxel in triple-negative breast cancer (TNBC) cell models. TR-107 also reduced specific mitochondrial proteins, including OXPHOS and TCA cycle components, in a time-, dose-, and ClpP-dependent manner. Seahorse XF analysis and glucose deprivation experiments confirmed the inactivation of OXPHOS and increased dependence on glycolysis following TR-107 exposure. The pharmacokinetic properties of TR-107 were compared with other known ClpP activators including ONC201 and ONC212. TR-107 displayed excellent exposure and serum t

Identifiants

DOI: 10.1002/prp2.993 PMID: 35929764 PMC: PMC9354705
pubmed: 35929764
doi: 10.1002/prp2.993
pmc: PMC9354705
doi:

Substances chimiques

Mitochondrial Proteins 0
Peptide Hydrolases EC 3.4.-
ClpP protein, human EC 3.4.21.92
Endopeptidase Clp EC 3.4.21.92

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, N.I.H., Intramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

e00993

Subventions

Organisme : Intramural NIH HHS
ID : ZIA SC007263
Pays : United States
Organisme : NIH HHS
ID : R35CA232113
Pays : United States
Organisme : NIH HHS
ID : T32CA009156
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA232113
Pays : United States
Organisme : NIH HHS
ID : 5R01GM138520-02
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM138520
Pays : United States

Informations de copyright

© 2022 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.

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Auteurs

Emily M J Fennell (EMJ)

Department of Pharmacology and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Lucas J Aponte-Collazo (LJ)

Department of Pharmacology and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Joshua D Wynn (JD)

Department of Pharmacology and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Kristina Drizyte-Miller (K)

Department of Pharmacology and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Elisa Leung (E)

Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.

Yoshimi Endo Greer (YE)

Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Paul R Graves (PR)

Department of Radiation Oncology, New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York, USA.

Andrew A Iwanowicz (AA)

Madera Therapeutics LLC, Chapel Hill, North Carolina, USA.

Hani Ashamalla (H)

Department of Radiation Oncology, New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York, USA.

Ekhson Holmuhamedov (E)

Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russian Federation.

Henk Lang (H)

Madera Therapeutics LLC, Chapel Hill, North Carolina, USA.

Donald S Karanewsky (DS)

Madera Therapeutics LLC, Chapel Hill, North Carolina, USA.

Channing J Der (CJ)

Department of Pharmacology and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Walid A Houry (WA)

Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
Department of Chemistry, University of Toronto, Toronto, Ontario, Canada.

Stanley Lipkowitz (S)

Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Edwin J Iwanowicz (EJ)

Madera Therapeutics LLC, Chapel Hill, North Carolina, USA.

Lee M Graves (LM)

Department of Pharmacology and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
ORCID: 0000-0002-4736-9855

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Classifications MeSH

Recherchemedicale.com › Eucaryotes › Animaux › Characterization of TR-107, a novel chemical...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines végétales › Protéines chloroplastiques › Endopeptidase Clp › Characterization of TR-107, a novel chemical...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Characterization of TR-107, a novel chemical...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Characterization of TR-107, a novel chemical...
Recherchemedicale.com › Cellules › Structures cellulaires › Fractions subcellulaires › Mitochondries › Characterization of TR-107, a novel chemical...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines mitochondriales › Characterization of TR-107, a novel chemical...
Recherchemedicale.com › Enzymes et coenzymes › Enzymes › Hydrolases › Peptide hydrolases › Characterization of TR-107, a novel chemical...
Recherchemedicale.com › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Maladies du sein › Tumeurs du sein › Tumeurs du sein triple-négatives › Characterization of TR-107, a novel chemical...