Author: Xiang, Xinrong ; Bao, Rui ; Zhou, Yuanzheng ; Luo, Baozhu ; Yang, Tao ; Sui, Jing ; Luo, Youfu ; Liu, Song ; Huang, Jiasheng ; Dai, Zhengyi ; Zhao, Ninglin ; Gu, Jinlong ; Zhang, Jiangnan

The activation of Homo sapiens Casein lysing protease P (HsClpP) by a chemical or genetic strategy has been proved to be a new potential therapy in acute myeloid leukemia (AML). However, limited efficacy has been achieved with classic agonist imipridone ONC201. Here, a novel class of HsClpP agonists is designed and synthesized using a ring-opening strategy based on the lead compound 1 reported in our previous study. Among these novel scaffold agonists, compound 7k exhibited remarkably enhanced proteolytic activity of HsClpP (EC₅₀ = 0.79 ± 0.03 μM) and antitumor activity in vitro (IC₅₀ = 0.038 ± 0.003 μM). Moreover, the intraperitoneal administration of compound 7k markedly suppressed tumor growth in Mv4-11 xenograft models, achieving a tumor growth inhibition rate of 88%. Concurrently, 7k displayed advantageous pharmacokinetic properties in vivo. This study underscores the promise of compound 7k as a significant HsClpP agonist and an antileukemia drug candidate, warranting further exploration for AML treatment.

01 Feb 2023·Structure

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

Article

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

The mitochondrial ClpP protease is responsible for mitochondrial protein quality control through specific degradation of proteins involved in several metabolic processes. ClpP overexpression is also required in many cancer cells to eliminate reactive oxygen species (ROS)-damaged proteins and to sustain oncogenesis. Targeting ClpP to dysregulate its function using small-molecule agonists is a recent strategy in cancer therapy. Here, we synthesized imipridone-derived compounds and related chemicals, which we characterized using biochemical, biophysical, and cellular studies. Using X-ray crystallography, we found that these compounds have enhanced binding affinities due to their greater shape and charge complementarity with the surface hydrophobic pockets of ClpP. N-terminome profiling of cancer cells upon treatment with one of these compounds revealed the global proteomic changes that arise and identified the structural motifs preferred for protein cleavage by compound-activated ClpP. Together, our studies provide the structural and molecular basis by which dysregulated ClpP affects cancer cell viability and proliferation.

01 Aug 2018·Cell Chemical BiologyQ1 · BIOLOGY

Acyldepsipeptide Analogs Dysregulate Human Mitochondrial ClpP Protease Activity and Cause Apoptotic Cell Death

Q1 · BIOLOGY

Article

Author: Yu Qian Mao ; Mohamed T. Moutaoufik ; Mark F. Mabanglo ; Larissa Hoell ; Keith S. Wong ; Kamran Rizzolo ; Thiago V. Seraphim ; Elisa Leung ; Robert A. Batey ; Carlos H.I. Ramos ; Antonio Mollica ; Sadhna Phanse ; Walid A. Houry ; Leandro R.S. Barbosa ; Aaron D. Schimmer ; Jordan Goodreid ; Mohan Babu ; Vito Mennella

Acyldepsipeptides (ADEPs) are potential antibiotics that dysregulate the activity of the highly conserved tetradecameric bacterial ClpP protease, leading to bacterial cell death. Here, we identified ADEP analogs that are potent dysregulators of the human mitochondrial ClpP (HsClpP). These ADEPs interact tightly with HsClpP, causing the protease to non-specifically degrade model substrates. Dysregulation of HsClpP activity by ADEP was found to induce cytotoxic effects via activation of the intrinsic, caspase-dependent apoptosis. ADEP-HsClpP co-crystal structure was solved for one of the analogs revealing a highly complementary binding interface formed by two HsClpP neighboring subunits but, unexpectedly, with HsClpP in the compact conformation. Given that HsClpP is highly expressed in multiple cancers and has important roles in cell metastasis, our findings suggest a therapeutic potential for ADEPs in cancer treatment.

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Indication	Highest Phase	Country/Location	Organization	Date
Leukemia	Preclinical	China	Sichuan University	15 Apr 2024

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