Harnessing the Magic Methyl Effect: Discovery of CLPP-2068 as a Novel <i>Hs</i>ClpP Activator for the Treatment of Diffuse Large B-Cell Lymphoma
The "magic methyl effect" has facilitated the successful development of numerous pharmaceutical compounds. During the development of <i>Hs</i>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, <b>CLPP-2068</b>, which exhibited an EC<sub>50</sub> 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 <b>CLPP-2068</b> and <i>Hs</i>ClpP, thereby lowering the energy barriers during the binding process. Furthermore, additional pharmaceutical analyses indicated that <b>CLPP-2068</b> exhibited favorable pharmacokinetic properties and effectively mitigated the potential hERG toxicity observed in imipridone-based <i>Hs</i>ClpP activators. Collectively, <b>CLPP-2068</b>, 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 <i>Hs</i>ClpP activators.
Authors
- Xinyi Lin (ORCID: https://orcid.org/0000-0002-9075-5364)
- Xingxing Diao (ORCID: https://orcid.org/0000-0002-6892-0861)
- Qi Huang (ORCID: https://orcid.org/0000-0003-1073-7471)
- Hongshen Zhao (ORCID: https://orcid.org/0000-0002-9246-0148)
- Mingliang Wang
- Xiaobei Hu (ORCID: https://orcid.org/0000-0002-7765-1771)
- Lei Xu (ORCID: https://orcid.org/0000-0003-2240-0737)
- Mingyue Zheng (ORCID: https://orcid.org/0000-0002-3323-3092)
- Jinghua Yu (ORCID: https://orcid.org/0000-0001-5043-0322)
- Beijing Chen (ORCID: https://orcid.org/0000-0002-2506-0427)
- Wanchao Yin (ORCID: https://orcid.org/0000-0002-6889-4907)
- Yubo Zhou (ORCID: https://orcid.org/0000-0002-0694-3697)
- Huicong Ma (ORCID: https://orcid.org/0000-0003-3678-3476)
- Fei Ye
- Jia Li (ORCID: https://orcid.org/0000-0003-3145-2811)
- Mingyang Sun (ORCID: https://orcid.org/0000-0003-3181-6793)
- Chongyu Wang (ORCID: https://orcid.org/0000-0002-6285-8446)
- Yu Peng (ORCID: https://orcid.org/0000-0003-2647-7627)
- Dan Teng
- Yilie Liao (ORCID: https://orcid.org/0009-0008-7122-8690)
- Qingning Yuan (ORCID: https://orcid.org/0009-0007-2979-5168)
- Chun Zhang (ORCID: https://orcid.org/0000-0001-7041-6958)
Institutions
- Zhejiang Sci-Tech University (CN)
- Zunyi Medical University (CN)
- Chinese Academy of Sciences (CN)
- Shanghai Institute of Materia Medica (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-02-12
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02016
- Citations
- 8
- Primary Topic
- Biochemical and Molecular Research
- Type
- article
- Field-Weighted Citation Impact
- 6.45
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Youth Innovation Promotion Association of the Chinese Academy of Sciences
- National Key Research and Development Program of China