Harnessing the Magic Methyl Effect: Discovery of CLPP-2068 as a Novel HsClpP Activator for the Treatment of Diffuse Large B-Cell Lymphoma

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 11, 2025

The "magic methyl effect" has facilitated the successful development of numerous pharmaceutical compounds. During HsClpP activators, we found that incorporating groups into bicyclic imipridone scaffolds significantly enhanced activator activity at enzymatic level. Further structure-activity relationship studies led to identification a highly promising compound, CLPP-2068, which exhibited an EC50 value 50.4 nM. Cryo-electron microscopy techniques and computational analyses demonstrated introduction formation additional CH-π interactions between CLPP-2068 HsClpP, thereby lowering energy barriers during binding process. Furthermore, indicated favorable pharmacokinetic properties effectively mitigated potential hERG toxicity observed in imipridone-based activators. Collectively, developed using magic methylation strategy, holds as therapeutic agent for treatment diffuse large B-cell lymphoma, expanding clinical indications

Language: Английский

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Discovery of Dehydrogenated Imipridone Derivatives as Activators of Human Caseinolytic Protease P

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(17), P. 15328 - 15352

Published: Aug. 22, 2024

Based on the founding member of imipridones, ONC201, a class dehydrogenated imipridone derivatives was designed, synthesized, and evaluated in series biochemical biological assays as human caseinolytic protease P (hClpP) activators. Mechanism studies for one most potent compounds, XT6, indicated that it can potently bind to both recombinant cellular hClpP, effectively promote formation hClpP tetradecamer, efficiently induce degradation substrates, robustly upregulate expression ATF4, strongly inhibit phosphorylations AKT ERK. More importantly, XT6 exhibited promising pharmacokinetic profile rats could penetrate blood brain barrier. It showed highly vivo antitumor activity MIAPACA2 cell line derived pancreatic cancer model BALB/c nude mice.

Language: Английский

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Patenting perspective of modulators of ClpP endopeptidase: 2019-present

Expert Opinion on Therapeutic Patents, Journal Year: 2024, Volume and Issue: 34(11), P. 1073 - 1084

Published: Sept. 13, 2024

ClpP is a highly conserved serine protease that plays crucial role in maintaining protein homeostasis both bacterial cells and human mitochondria. Several studies have demonstrated the potential of as drug target, with modulators, including inhibitors activators, showing promise treating range conditions such drug-resistant bacteria, malignant cancers, fatty liver disease.

Language: Английский

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Discovery of CLPP-1071 as an Exceptionally Potent and Orally Efficacious Human ClpP Activator with Strong In Vivo Antitumor Activity

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 22, 2024

caseinolytic protease P (ClpP) is essential for maintaining mitochondrial proteome homeostasis, and its activation increasingly recognized as a promising cancer therapy strategy. Herein, based on structure-guided drug design, we discovered series of potent ClpP activators by introducing methyl group to the imipridone scaffold activator

Language: Английский

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Chemical activation of mitochondrial ClpP to modulate energy metabolism of CD4+ T cell for inflammatory bowel diseases treatment

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(12), P. 101840 - 101840

Published: Dec. 1, 2024

Language: Английский

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