Evidence map›Paper›PMID 39946082›Full record

ArticleMolecular diversity2025

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

Abstract read
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In one paragraph

Article in Molecular diversity, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors.

Yiming WenSchool of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 330106, China.
Peijia XuSchool of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 330106, China.
Yijie ChenState 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.
Jingyi MengState 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.
Mingyue ZhengSchool of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 330106, China.
Sulin ZhangState 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.
Dan TengState 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.
Xutong LiState 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.

Funding

China Postdoctoral Science Foundation 2024M763419National Key Research and Development Program of China 2022YFC3400504National Natural Science Foundation of China 82204278National Natural Science Foundation of China T2225002Postdoctoral Fellowship Program of CPSF GZC20232846SIMM-SHUTCM Traditional Chinese Medicine Innovation Joint Research Program E2G805HStrategic Priority Research Program of the Chinese Academy of sciences XDB0830200Strategic Priority Research Program of the Chinese Academy of sciences XDB0830203the Youth Innovation Promotion Association CAS 2023296
6 · The paper itself

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.

Indexed as

Drug DiscoveryTumor Suppressor Protein p53HumansIndolesMolecular Dynamics SimulationMutationProtein BindingProtein StabilityStructure-Activity RelationshipIndolesTumor Suppressor Protein p53Cancer therapyCovalent stabilizerDNA bindingMolecular dynamicsp53 Y220CStructure–activity relationshipVirtual screening

Identifiers

PMID39946082

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.