Potent ClpP agonists with anticancer properties bind with improved structural complementarity and alter the mitochondrial N-terminome

Mabanglo, Mark; Wong, Keith S.; Barghash, Marim; Leung, Eman; Chuang, Stephanie H W; Ardalan, Afshan; Majaesic, Emily; Wong, Cassandra; Zhang, Shen; Lang, Henk; Karanewsky, Donald S.; Iwanowicz, Andrew A.; Graves, Lee M.; Iwanowicz, Edwin J.; Gingras, Anne‐Claude; Houry, Walid

doi:10.1016/j.str.2022.12.002

Cited by 19 publications

(23 citation statements)

References 55 publications

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“…Another evolving approach to targeting mitochondrial transcription includes the recently discovered small molecule activators of the mitochondrial protease ClpP (herein referred to as ClpP agonists). These compounds include the imipridones ONC201 and ONC206 (currently in clinical trials), the more potent TR compounds, and other recently discovered molecules [ 33 , 34 , 35 , 36 , 37 ]. Studies from our laboratory and others show that ClpP agonists rapidly deplete POLRMT protein and other key proteins involved in mtDNA transcription [ 33 , 34 , 35 , 38 ].…”

Section: Mitochondrial Transcription and Metabolism As Targets For Ne...mentioning

confidence: 99%

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

2023

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Transcription of the mitochondrial genome is essential for the maintenance of oxidative phosphorylation (OXPHOS) and other functions directly related to this unique genome. Considerable evidence suggests that mitochondrial transcription is dysregulated in cancer and cancer metastasis and contributes significantly to cancer cell metabolism. Recently, inhibitors of the mitochondrial DNA-dependent RNA polymerase (POLRMT) were identified as potentially attractive new anti-cancer compounds. These molecules (IMT1, IMT1B) inactivate cancer cell metabolism through reduced transcription of mitochondrially-encoded OXPHOS subunits such as ND1-5 (Complex I) and COI-IV (Complex IV). Studies from our lab have discovered small molecule regulators of the mitochondrial matrix caseinolytic protease (ClpP) as probable inhibitors of mitochondrial transcription. These compounds activate ClpP proteolysis and lead to the rapid depletion of POLRMT and other matrix proteins, resulting in inhibition of mitochondrial transcription and growth arrest. Herein we present a comparison of POLRMT inhibition and ClpP activation, both conceptually and experimentally, and evaluate the results of these treatments on mitochondrial transcription, inhibition of OXPHOS, and ultimately cancer cell growth. We discuss the potential for targeting mitochondrial transcription as a cancer cell vulnerability.

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Section: Mitochondrial Transcription and Metabolism As Targets For Ne...mentioning

confidence: 99%

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

2023

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“…Similar to ADEPs, imipridones directly binds to ClpP, and displace ClpX, and the bindings triggers the opening of channel-like pore of ClpP, and thereby increase its protease activity without the ClpX [ 233 , 271 , 293 ] ( Figure 6 B). Recently, X-ray crystallography demonstrated that TR compounds bind to ClpP, with enhanced binding affinities due to their greater shape and charge complementarity with the surface hydrophobic pockets of ClpP [ 294 ] ( Figure 7 C). Moreover, N-terminome profiling of MDA-MB-231 cell line upon treatment with one of TR compounds revealed the global proteomic changes and characterized the sequence and structural properties for protein cleavage generated upon TR compound-induced ClpP-dependent proteolysis of cellular proteins [ 294 ].…”

Section: Clppmentioning

confidence: 99%

“…Compared with imipridones, TR compounds show significantly higher potency; IC 50 of TR-57 and TR-107 exert anti-proliferative effects in the 10–25 nanomolar in TNBC cells ( Table 2 ). The superior potency of TR compounds over other ClpP agonists is attributed to the better binding properties to ClpP [ 294 ].…”

Section: Preclinical Studies Using Clpp Agonists In Breast Cancersmentioning

confidence: 99%

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

Wedam

Greer

Wisniewski

et al. 2023

Cancers

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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.

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“…Typically, ClpP activators have similar structural characteristics. They usually consist of a hydrophobic group at both ends and a supportive scaffold in the middle, forming a “clamp” that binds to the ClpP groove. ,− For example, the substituted phenyl groups at both ends of CCG1423 are embedded in the hydrophobic cavity as clamp A and clamp B, respectively (Figure F). Dependent on the intermediate α-aminooxypropionic acid, the compound constitutes a structure spatially complementary to the surface of the ClpP groove (Figure E,F).…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Series of Homo sapiens Caseinolytic Protease P Agonists for Colorectal Adenocarcinoma Treatment via ATF3-Dependent Integrated Stress Response

Zhang,

Qiu,

Liu

et al. 2024

J. Med. Chem.

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Homo sapiens caseinolytic protease P (HsClpP) activation is a promising strategy for colon cancer treatment. In this study, CCG1423 was identified as a selective activator of HsClpP. After optimization, NCA029 emerged as the most potent compound, with an EC 50 of 0.2 μM against HsClpP. Molecular dynamics revealed that the affinity of NCA029 for the YYW aromatic network is crucial for its selectivity toward HsClpP. Furthermore, NCA029 displayed favorable pharmacokinetics and safety profiles and significantly inhibited tumor growth in HCT116 xenografts, resulting in 83.6% tumor inhibition. Mechanistically, NCA029 targeted HsClpP, inducing mitochondrial dysfunction and activating the ATF3-dependent integrated stress response, ultimately causing cell death in colorectal adenocarcinoma. These findings highlight NCA029 as an effective HsClpP activator with potential for colon cancer therapy.

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Potent ClpP agonists with anticancer properties bind with improved structural complementarity and alter the mitochondrial N-terminome

Cited by 19 publications

References 55 publications

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

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

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

Discovery of a Novel Series of Homo sapiens Caseinolytic Protease P Agonists for Colorectal Adenocarcinoma Treatment via ATF3-Dependent Integrated Stress Response

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