Targeting the TRIM28-EZH2 Protein-Protein Interface With Cysteine-Reactive Covalent Inhibitors: A Computational Blueprint for Cancer Therapy.

Ibrahim Oluwatobi Kehinde, Vuyisa Mzozoyana, Sizwe J Zamisa, Mbuso Faya, Mahmoud E S Soliman

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Article in Chemistry & biodiversity, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

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1citing papers in PubMed

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1 · What the graph read from it

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1 citing paper in PubMed.

Targeting the TRIM28-EZH2 Protein-Protein Interface With Cysteine-Reactive Covalent Inhibitors: A Computational Blueprint for Cancer Therapy.Chemistry & biodiversity · 2026
Article

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5 · Who and what money

Authors and funding

5 authors.

Ibrahim Oluwatobi KehindeMolecular Bio-Computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.ORCID https://orcid.org/0000-0002-9425-0267

Vuyisa MzozoyanaSchool of Chemistry and Physics, Westville Campus, University of KwaZulu-Natal, Durban, South Africa.

Sizwe J ZamisaSchool of Chemistry and Physics, Westville Campus, University of KwaZulu-Natal, Durban, South Africa.

Mbuso FayaDiscipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.

Mahmoud E S SolimanMolecular Bio-Computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.ORCID https://orcid.org/0000-0002-8711-7783

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Aberrant protein-protein interactions (PPIs) play crucial roles in cancer progression by driving transcriptional repression and epigenetic silencing. Among these, the TRIM28-EZH2 interaction is central to maintaining repressive chromatin states that promote tumorigenesis. In this study, we modeled the TRIM28-EZH2 complex using protein-protein docking, revealing a stable interface dominated by the RBCC domain of TRIM28 and the PRC2 catalytic domain of EZH2. A cysteine-focused covalent inhibitor library was screened to identify small molecules capable of targeting reactive cysteines at the interface. Four lead compounds were identified, with compound C87 exhibiting the most favorable binding free energy (ΔG

Indexed as

Antineoplastic AgentsCysteineEnhancer of Zeste Homolog 2 ProteinSmall Molecule LibrariesTripartite Motif-Containing Protein 28HumansMolecular Docking SimulationMolecular Dynamics SimulationMolecular StructureNeoplasmsProtein BindingStructure-Activity RelationshipAntineoplastic AgentsCysteineEnhancer of Zeste Homolog 2 ProteinEZH2 protein, humanSmall Molecule LibrariesTRIM28 protein, humanTripartite Motif-Containing Protein 28cancercovalent dockingcovalent molecular dynamics simulationEZH2protein–protein interactionTRIM28

Identifiers

PMID41504013

DOI10.1002/cbdv.202502892

PMCPMC12781155

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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.