De novo discovery of a molecular glue–like macrocyclic peptide that induces MCL1 homodimerization

Macrocyclic peptides have emerged as promising drug candidates, filling the gap between small molecules and large biomolecules in drug discovery. The antiapoptotic protein myeloid cell leukemia 1 (MCL1) is crucial for numerous cancers, yet it presents challenges for selective targeting by traditional inhibitors. In this study, we identified a macrocyclic peptide, 5L1, that strongly binds to MCL1, with a dissociation constant (<i>K<sub>D</sub></i>) of 7.1 nM. This peptide shows the potential to specifically inhibit the function of MCL1, and demonstrates effective antitumor activity against several blood tumor cell lines with the half maximal inhibitory concentration (IC<sub>50</sub>) values for cell-penetrating peptide-conjugated 5L1 in the range of 0.6 to 3 μM. Structural analysis revealed that it functions similarly to molecular glue, capable of binding to two MCL1 molecules simultaneously and inducing their homodimerization. This unique mechanism of action distinguishes it from traditional small-molecule MCL1 inhibitors, underscoring the potential of macrocyclic peptides functioning as molecular glues. Moreover, it inspires the development of highly selective inhibitors targeting MCL1 and other related targets with this glue-like mechanism.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-03-25
DOI
https://doi.org/10.1073/pnas.2426006122
Citations
3
Primary Topic
Chemical Synthesis and Analysis
Type
article
Field-Weighted Citation Impact
2.42

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article

De novo discovery of a molecular glue–like macrocyclic peptide that induces MCL1 homodimerization

You‐Ming Zhang, Yuyu Guo, Yizhen Yin, Dalei Wu et al.
3 citations
Proceedings of the National Academy of Sciences
Chemical Synthesis and Analysis
2.42
article

De novo discovery of a molecular glue–like macrocyclic peptide that induces MCL1 homodimerization

You‐Ming Zhang, Yuyu Guo, Yizhen Yin, Dalei Wu, Jie Cheng, Wenfeng Cai, Junjie Wu, Chao Liu, Haipeng Yu, Xiangda Peng, Mengmeng Zhang, Yawen Yang, Zhifeng Li, Hui Geng, Fengwei Li, Yun Fa
article en
3 citations

Abstract

Macrocyclic peptides have emerged as promising drug candidates, filling the gap between small molecules and large biomolecules in drug discovery. The antiapoptotic protein myeloid cell leukemia 1 (MCL1) is crucial for numerous cancers, yet it presents challenges for selective targeting by traditional inhibitors. In this study, we identified a macrocyclic peptide, 5L1, that strongly binds to MCL1, with a dissociation constant (<i>K<sub>D</sub></i>) of 7.1 nM. This peptide shows the potential to specifically inhibit the function of MCL1, and demonstrates effective antitumor activity against several blood tumor cell lines with the half maximal inhibitory concentration (IC<sub>50</sub>) values for cell-penetrating peptide-conjugated 5L1 in the range of 0.6 to 3 μM. Structural analysis revealed that it functions similarly to molecular glue, capable of binding to two MCL1 molecules simultaneously and inducing their homodimerization. This unique mechanism of action distinguishes it from traditional small-molecule MCL1 inhibitors, underscoring the potential of macrocyclic peptides functioning as molecular glues. Moreover, it inspires the development of highly selective inhibitors targeting MCL1 and other related targets with this glue-like mechanism.

Proceedings of the National Academy of SciencesVol. 122(13)
Energy Institute (GB), Shandong University (CN), Waters (United States) (US), Waters (China) (CN), Jinan Institute of Quantum Technology (CN), Institute of Microbial Technology (IN), Ecologie microbienne (FR), Qingdao Institute of Bioenergy and Bioprocess Technology (CN), Wyatt Technology (China) (CN)
Shandong University, Salt Science Research Foundation, National Natural Science Foundation of China, China Postdoctoral Science Foundation, Natural Science Foundation of Shandong Province
Good health and well-being
Openalex Percentile: Top 12%
Chemical Synthesis and Analysis
2.42
DOIOpen Access PDFOpenAlex
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