Evidence map›Paper›PMID 40994151›Full record

ArticleJournal of the American Chemical Society2025

Indolequinone-Based Hypoxia-Activated Proteolysis Targeting Chimeras Selectively Degrade BRD4 in Hypoxic Cancer Cells.

Marta Serafini, Sophie A Twigger, George Delfas, Maxim Mallerman, Elliot P Bailey, Ewen D D Calder, Ester M Hammond, Stuart J Conway

Abstract read
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In one paragraph

Article in Journal of the American Chemical Society, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing 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

8 citing papers in PubMed.

  1. Evolving CRBN ligands enhance the drug-like properties of protein degraders.Journal of enzyme inhibition and medicinal chemistry · 2026
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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.

Marta SerafiniDepartment of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.ORCID 0000-0002-5305-8359
Sophie A TwiggerDepartment of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, U.K.
George DelfasDepartment of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
Maxim MallermanDepartment of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
Elliot P BaileyDepartment of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
Ewen D D CalderDepartment of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.ORCID 0000-0001-7201-8451
Ester M HammondDepartment of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, U.K.ORCID 0000-0002-2335-3146
Stuart J ConwayDepartment of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.ORCID 0000-0002-5148-117X

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Proteolysis targeting chimeras (PROTACs) have helped to establish proximity induction as an exciting strategy in drug discovery, and there are multiple clinical trials focused on this modality. However, degradation of a full protein in a physiological setting might lead to dose-limiting toxicities, giving rise to the need for PROTACs that are activated in a context-dependent nature. Here, we report the development of hypoxia-activated PROTACs (HAP-TACs) which are selectively activated in conditions of low oxygen (hypoxia) such as those found in solid tumors. To develop HAP-TACs, we have attached an indolequinone bioreductive group to an essential functional group of either the VHL- or cereblon-recruiting component of the PROTAC, reducing affinity for its cognate E3 ligase and preventing degradation of the protein of interest. Using BRD4, we have conducted proof-of-concept studies which demonstrate that the indolequinone group is bioreduced under hypoxic conditions, releasing the active PROTAC, resulting in selective degradation of BRD4 in hypoxia. As the bioreductive group is attached to the VHL or cereblon ligand, this approach is potentially applicable to all PROTACs that recruit these commonly employed E3 ligases.

Indexed as

Cell Cycle ProteinsIndolequinonesProteolysisTranscription FactorsAdaptor Proteins, Signal TransducingBromodomain Containing ProteinsCell HypoxiaCell Line, TumorHumansProteolysis Targeting ChimeraUbiquitin-Protein LigasesVon Hippel-Lindau Tumor Suppressor ProteinAdaptor Proteins, Signal TransducingBRD4 protein, humanBromodomain Containing ProteinsCell Cycle ProteinsCRBN protein, humanIndolequinonesProteolysis Targeting ChimeraTranscription FactorsUbiquitin-Protein LigasesVHL protein, humanVon Hippel-Lindau Tumor Suppressor Protein

Identifiers

PMID40994151
PMCPMC12512183

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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.