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TitleHarnessing the Magic Methyl Effect: Discovery of CLPP-2068 as a Novel ClpP Activator for the Treatment of Diffuse Large B-Cell Lymphoma.
Journal, issue, pagesJ Med Chem, Vol. 68, Issue 4, Page 4287-4307, Year 2025
Publish dateFeb 27, 2025
AuthorsMingyang Sun / Beijing Chen / Dan Teng / Hongshen Zhao / Yilie Liao / Chun Zhang / Qi Huang / Huicong Ma / Chongyu Wang / Xinyi Lin / Peng Yu / Qingning Yuan / Jinghua Yu / Lei Xu / Xiaobei Hu / Fei Ye / Xingxing Diao / Mingyue Zheng / Wanchao Yin / Yubo Zhou / Jia Li / Mingliang Wang /
PubMed AbstractThe "magic methyl effect" has facilitated the successful development of numerous pharmaceutical compounds. During the development of ClpP activators, we found that incorporating methyl groups into ...The "magic methyl effect" has facilitated the successful development of numerous pharmaceutical compounds. During the development of ClpP activators, we found that incorporating methyl groups into the bicyclic imipridone scaffolds significantly enhanced the activator activity at the enzymatic level. Further structure-activity relationship studies led to the identification of a highly promising compound, , which exhibited an EC value of 50.4 nM. Cryo-electron microscopy techniques and computational analyses demonstrated that the introduction of methyl groups facilitated the formation of additional CH-π interactions between and ClpP, thereby lowering the energy barriers during the binding process. Furthermore, additional pharmaceutical analyses indicated that exhibited favorable pharmacokinetic properties and effectively mitigated the potential hERG toxicity observed in imipridone-based ClpP activators. Collectively, , developed using the magic methylation strategy, holds potential as a therapeutic agent for the treatment of diffuse large B-cell lymphoma, thereby expanding the clinical indications for ClpP activators.
External linksJ Med Chem / PubMed:39935096
MethodsEM (single particle)
Resolution2.45 Å
Structure data

62577

9kuf

EMDB-62577, PDB-9kuf:
Cryo-EM structure of HsClpP bound to CLPP-2068
Method: EM (single particle) / Resolution: 2.45 Å

Chemicals

PDB-1eg3:
STRUCTURE OF A DYSTROPHIN WW DOMAIN FRAGMENT IN COMPLEX WITH A BETA-DYSTROGLYCAN PEPTIDE

Source
  • homo sapiens (human)
KeywordsANTITUMOR PROTEIN / ClpP / CLPP-2068 / bicyclic imipridone / methyl groups / Diffuse Large B-Cell Lymphoma / Cryo-EM

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