9KUF

Cryo-EM structure of HsClpP bound to CLPP-2068

This is a non-PDB format compatible entry.

Summary for 9KUF

• Entry DOI: 10.2210/pdb9kuf/pdb
• EMDB information: 62577
• Descriptor: ATP-dependent Clp protease proteolytic subunit, mitochondrial, 3-[[(7~{R})-2-[(4-bromophenyl)methylamino]-7-methyl-4-oxidanylidene-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]methyl]benzenecarbonitrile (2 entities in total)
• Functional Keywords: clpp, clpp-2068, bicyclic imipridone, methyl groups, diffuse large b-cell lymphoma, cryo-em, antitumor protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 14
• Total formula weight: 342215.93

Authors

Zhao, H.,Yuan, Q.,Yin, W. (deposition date: 2024-12-03, release date: 2025-07-16, Last modification date: 2025-07-30)

Primary citation

Sun, M.,Chen, B.,Teng, D.,Zhao, H.,Liao, Y.,Zhang, C.,Huang, Q.,Ma, H.,Wang, C.,Lin, X.,Yu, P.,Yuan, Q.,Yu, J.,Xu, L.,Hu, X.,Ye, F.,Diao, X.,Zheng, M.,Yin, W.,Zhou, Y.,Li, J.,Wang, M.
Harnessing the Magic Methyl Effect: Discovery of CLPP-2068 as a Novel HsClpP Activator for the Treatment of Diffuse Large B-Cell Lymphoma.
J.Med.Chem., 68:4287-4307, 2025

PubMed Abstract: 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.

PubMed: 39935096
DOI: 10.1021/acs.jmedchem.4c02016

Experimental method

ELECTRON MICROSCOPY (2.45 Å)