Evidence map›Paper›PMID 38746397›Full record

ArticlebioRxiv : the preprint server for biology2024

Paralogue-selective degradation of the lysine acetyltransferase EP300.

Xuemin Chen, McKenna C Crawford, Ying Xiong, Anver Basha Shaik, Kiall F Suazo, Manini S Penkalapati, Joycelyn H Williams, Thorkell Andressen, Rolf E Swenson, Jordan L Meier

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

10 authors.

Xuemin ChenChemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA.ORCID 0000-0002-0860-4365
McKenna C CrawfordChemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA.ORCID 0000-0002-3274-1255
Ying XiongChemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA.ORCID 0009-0009-8835-202X
Anver Basha ShaikChemistry and Synthesis Center, National Heart Lung and Blood Institute, Bethesda, MD, USA.ORCID 0000-0001-9894-5544
Kiall F SuazoChemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA.ORCID 0000-0002-0803-8332
Manini S PenkalapatiChemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA.
Joycelyn H WilliamsChemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA.
Thorkell AndressenProtein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD, USA.ORCID 0000-0002-9545-2450
Rolf E SwensonChemistry and Synthesis Center, National Heart Lung and Blood Institute, Bethesda, MD, USA.ORCID 0000-0001-7804-7202
Jordan L MeierChemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA.ORCID 0000-0002-0537-7101

Funding

Targeting Cancer Through Modifications and MetabolismZIABC011488 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI MEIER, JORDAN L · 2013 to 2025
$21.3M
Intramural NIH HHS ZIA BC011488
6 · The paper itself

Abstract

The transcriptional coactivators EP300 and CREBBP are critical regulators of gene expression that share high sequence identity but exhibit non-redundant functions in basal and pathological contexts. Here, we report the development of a bifunctional small molecule, MC-1, capable of selectively degrading EP300 over CREBBP. Using a potent aminopyridine-based inhibitor of the EP300/CREBBP catalytic domain in combination with a VHL ligand, we demonstrate that MC-1 preferentially degrades EP300 in a proteasome-dependent manner. Mechanistic studies reveal that selective degradation cannot be predicted solely by target engagement or ternary complex formation, suggesting additional factors govern paralogue-specific degradation. MC-1 inhibits cell proliferation in a subset of cancer cell lines and provides a new tool to investigate the non-catalytic functions of EP300 and CREBBP. Our findings expand the repertoire of EP300/CREBBP-targeting chemical probes and offer insights into the determinants of selective degradation of highly homologous proteins.

Identifiers

PMID38746397
PMCPMC11092752

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

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.