Targeting Mitochondria with ClpP Agonists as a Novel Therapeutic Opportunity in Breast Cancer

Abstract

Breast cancer is the most frequently diagnosed malignancy worldwide and the leading cause of cancer mortality in women. Despite the recent development of new therapeutics including targeted therapies and immunotherapy, triple-negative breast cancer remains an aggressive form of breast cancer, and thus improved treatments are needed. In recent decades, it has become increasingly clear that breast cancers harbor metabolic plasticity that is controlled by mitochondria. A myriad of studies provide evidence that mitochondria are essential to breast cancer progression. Mitochondria in breast cancers are widely reprogrammed to enhance energy production and biosynthesis of macromolecules required for tumor growth. In this review, we will discuss the current understanding of mitochondrial roles in breast cancers and elucidate why mitochondria are a rational therapeutic target. We will then outline the status of the use of mitochondria-targeting drugs in breast cancers, and highlight ClpP agonists as emerging mitochondria-targeting drugs with a unique mechanism of action. We also illustrate possible drug combination strategies and challenges in the future breast cancer clinic.

Targeting Mitochondrial DNA Transcription by POLRMT Inhibition or Depletion as a Potential Strategy for Cancer Treatment

“…Recently, a novel class of mitochondria-targeting drugs were discovered based on their highly unusual property of activating the mitochondrial protease ClpP. For in-depth reviews on pharmacological ClpP activation see Wong and Houry (2019) and Wedam et al [ 61 , 62 ]. ONC201 was first identified as a potential anti-cancer compound in a screen for small molecule inducers of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) [ 37 ].…”

“…There are a few known cancer cell mechanisms of resistance to ClpP agonists, including p 0 cells, fumarate hydratase knockout cell lines, and ClpP knockout or ClpP mutant cell lines [ 61 ]. The specific ClpP mutation, D190A, is known to confer resistance to ClpP agonists [ 68 ].…”

Dual target effect of hemiprotonic phenoline-phenoline+ on inhibiting metastatic breast cancer and concurrent candidiasis

“…The protease is responsible for protein homeostasis by degradation of misfolded and damaged proteins. In malignant tumors, expression and activity of CLpP remarkably increased relative to non-malignant cells [52,53] In conclusion, here we suggested a feasible approach to suppress metastatic breast cancer and concurrent candidiasis. Molecular mechanism of ph-ph + in antibacterial and anticancer could be related to the activation of mitochondrial protease CLpP, which will lead to cell energy de ciency.…”

Discovery and Mechanistic Study of Novel Mycobacterium tuberculosis ClpP1P2 Inhibitors

“…The ClpP system represents a unique type of serine protease complex responsible for the proteolysis of damaged or misfolded proteins that serves as a critical regulator of protein turnover and proteome homeostasis. ClpPs are involved in a range of human diseases and play a vital role in many bacterial infections; − therefore, interfering with ClpP function is regarded as a promising therapeutic strategy in the treatment of numerous disorders. , Herein, we identified cediranib as a novel structural class for MtbClpP1P2 inhibition with antitubercular activity in vitro. Using biophysical approaches, we evaluated the interactions between cediranib derivatives and MtbClpP1P2.…”