Open AccessCharacterization of TR ‐107, a novel chemical activator of the human mitochondrial protease ClpP
Author(s) -
Fennell Emily M. J.,
AponteCollazo Lucas J.,
Wynn Joshua D.,
DrizyteMiller Kristina,
Leung Elisa,
Greer Yoshimi Endo,
Graves Paul R.,
Iwanowicz Andrew A.,
Ashamalla Hani,
Holmuhamedov Ekhson,
Lang Henk,
Karanewsky Donald S.,
Der Channing J.,
Houry Walid A.,
Lipkowitz Stanley,
Iwanowicz Edwin J.,
Graves Lee M.
Publication year - 2022
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.993
Subject(s) - in vivo , tfam , chemistry , pharmacology , in vitro , potency , triple negative breast cancer , protease , biochemistry , biology , microbiology and biotechnology , cancer research , cancer , mitochondrion , breast cancer , enzyme , mitochondrial biogenesis , genetics
Abstract 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 1/2 after oral administration. Using human TNBC MDA‐MB‐231 xenografts, the antitumor response to TR‐107 was investigated. Oral administration of TR‐107 resulted in a reduction in tumor volume and extension of survival in the treated compared with vehicle control mice. ClpP activation in vivo was validated by immunoblotting for TFAM and other mitochondrial proteins. In summary, we describe the identification of highly potent new ClpP agonists with improved efficacy against TNBC, through targeted inactivation of OXPHOS and disruption of mitochondrial metabolism.