CLPP (Caseinolytic Mitochondrial Matrix Peptidase Proteolytic Subunit)

Dordaviprone (ONC201) and its chemical derivative with nanomolar potency, ONC206, induce apoptosis of cancer cells by activation of the mitochondrial caseinolytic protease P (ClpP). We also saw that ONC206 very significantly prolonged survival of medulloblastoma-bearing mice, both in genetically engineered mouse models and patient-derived xenografts. Our study provides a strong rationale for testing the efficacy of ONC206 in the treatment of patients with medulloblastoma and has set the stage for a clinical trial with this agent in pediatric patients with recurrent malignant brain tumors, including medulloblastoma ( NCT04732065 ).

Mechanistically, circLPP upregulated Wnt3a expression and activated the Wnt/β-catenin signaling pathway by sponging miR-665. Our findings revealed that circLPP driven CRC progression by modulating the Wnt/β-catenin pathway, highlighting its potential as a therapeutic target for CRC.

We provide an overview about the mechanistic rationale behind ClpP agonists as novel anticancer drugs, their regulation in cell signal transduction, and the major challenge in the creation of small molecules that specifically activate human ClpP, but not bacterial ClpP. The review highlights the therapeutic promise of ClpP agonists as a novel approach in cancer therapy, presenting their prospective potential for cancer treatment by focusing on an unexplored mitochondrial target.

Thus, ClpP is a novel addiction of MM cells, whose inhibition not only exerts cell-intrinsic toxicity, but also triggers otherwise indolent anti-tumoral immunity. Our findings yield a novel immunogenic chemotherapeutic framework of potential relevance against myeloma.

Conversely, hyperactivating ClpP with small-molecule activators, such as the recently discovered ONC201, disrupts mitochondrial protein degradation and impairs respiration in cancer cells...We elucidate the ClpP activation mechanism, highlighting a hormetic effect where substoichiometric inhibitor binding triggers an allosteric transition that drives ClpP into its active extended state. Our findings link the conformational dynamics of ClpP to its catalytic function and provide high-resolution structures for the rational design of potent and specific ClpP inhibitors, with implications for targeting AML and other disorders with ClpP involvement.

Notably, 7b also showed efficacy against drug-resistant MM cell lines, including bortezomib- and lenalidomide-resistant cells. In vivo, 7b also exhibited remarkable anti-MM activity with tolerable side effects. In conclusion, targeting ClpP represents a promising therapeutic strategy for MM, with 7b serving as a potent anti-MM agent, especially for relapsed and refractory MM.

The results suggest that treatment of castrate-resistant prostate cancer by imipridones may not be substantially affected by neuroendocrine differentiation as a therapy-resistance mechanism. The results support further testing of imipridones across subtypes of androgen-sensitive and castrate-resistant prostate cancer.

Imipridones are a promising strategy for further testing and development in mUM.

The results support the idea that treatment of castrate-resistant prostate cancer by imipridones may not be significantly impacted by neuroendocrine differentiation as a therapy-resistance mechanism. The results support further testing of imipridones across subtypes of androgen-sensitive and castrate-resistant prostate cancer.

Our results have relevance to activity of ONC201 in PCa where most castrate-resistant androgen-independent cancers are not therapy resistant due to NET differentiation. Importantly, NET differentiation does not promote resistance to ONC201 supporting further clinical investigations across the spectrum of PCa.

In conclusion, CLPP increases DDP resistance in ovarian cancer by inhibiting mitophagy and promoting cellular stress. Meanwhile, HSPA8 promotes the degradation of CLPP protein by regulating its stability.

Crystal structures show cystargolide A covalently bound to all 14 active sites of ClpP from S. aureus, Aquifex aeolicus, as well as Photorhabdus laumondii, and reveal the molecular mechanism of ClpP inhibition by β-lactones, the pioneering group of ClpP inhibitors.