Discovery of novel covalent stabilizers for p53 Y220C using structure-based drug discovery methods

Yiming Wen; Peijia Xu; Yijie Chen; Jingyi Meng; Mingyue Zheng; Sulin Zhang; Dan Teng; Xutong Li

doi:10.1007/s11030-024-11095-1

Discovery of novel covalent stabilizers for p53 Y220C using structure-based drug discovery methods

Mol Divers. 2025 Feb 13. doi: 10.1007/s11030-024-11095-1. Online ahead of print.

Authors

Yiming Wen^{1

2

3

4}, Peijia Xu^{1

5}, Yijie Chen^{2

6}, Jingyi Meng^{2

6}, Mingyue Zheng^{1

2

6

4}, Sulin Zhang^{2

4}, Dan Teng^{7

8}, Xutong Li^{9

10}

Affiliations

¹ School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 330106, China.
² State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
³ School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
⁴ University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
⁵ School of Pharmacy, East China Normal University, Shanghai, 200241, China.
⁶ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China.
⁷ State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. tengdan@simm.ac.cn.
⁸ University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. tengdan@simm.ac.cn.
⁹ State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. lixutong@simm.ac.cn.
¹⁰ University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. lixutong@simm.ac.cn.

PMID: 39946082
DOI: 10.1007/s11030-024-11095-1

Abstract

The p53 Y220C mutation, a prevalent structural variant in human cancers, compromises DNA binding and tumor suppressor functions by destabilizing the protein structure. Leveraging a combined approach of structure-based virtual screening, molecular dynamics simulations, and in vitro assays, we have identified C8, a racemic compound with an indole core and α, β-unsaturated carbonyl groups, as a covalent stabilizer for p53 Y220C. Protein thermal shift and homogeneous time-resolved fluorescence assays confirmed that C8 and its analogs selectively bind to p53 Y220C and restore its DNA binding ability. Subsequent molecular dynamics simulations and structure-activity relationship analyses showed that both enantiomers of C8 form covalent bonds with Cys124 and Cys220, stabilizing the mutant structure. C8 and its analogs emerge as promising lead candidates for restoring the Y220C mutant's transcriptional function, highlights the potential of this scaffold for further optimization into p53 Y220C-targeted therapeutics.

Keywords: Cancer therapy; Covalent stabilizer; DNA binding; Molecular dynamics; Structure–activity relationship; Virtual screening; p53 Y220C.

Abstract

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