Evidence map›Paper›PMID 42642754›Full record

ArticleChemMedChem2026

Structure-Guided Optimization of a Molecular Glue Targeting the KBTBD4-HDAC1/2 Complex.

Timea Balo, Zhuoyao Chen, Laurine Palluaud, Arpad Kiss, Tibor Novak, Andras Herner, Alex N Bullock, Virginie Martiny, Andras Kotschy

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in ChemMedChem, 2026. 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

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

9 authors.

Timea BaloServier Research Institute of Medicinal Chemistry, Budapest, Hungary.ORCID https://orcid.org/0009-0009-4013-8243
Zhuoyao ChenCentre for Medicines Discovery, University of Oxford, Oxford, UK.ORCID https://orcid.org/0000-0003-4201-4649
Laurine PalluaudServier Research Institute of Medicinal Chemistry, Budapest, Hungary.ORCID https://orcid.org/0009-0009-2400-9169
Arpad KissServier Research Institute of Medicinal Chemistry, Budapest, Hungary.
Tibor NovakServier Research Institute of Medicinal Chemistry, Budapest, Hungary.
Andras HernerServier Research Institute of Medicinal Chemistry, Budapest, Hungary.ORCID https://orcid.org/0009-0005-1406-3971
Alex N BullockCentre for Medicines Discovery, University of Oxford, Oxford, UK.ORCID https://orcid.org/0000-0001-6757-0436
Virginie MartinyServier R&D Institute, Gif-sur-Yvette, France.ORCID https://orcid.org/0000-0002-6866-3957
Andras KotschyServier Research Institute of Medicinal Chemistry, Budapest, Hungary.ORCID https://orcid.org/0000-0002-7675-3864

Funding

Innovative Medicines Initiative 875510Richter Gedeon Talentum Alapítvány
6 · The paper itself

Abstract

Optimization of UM171, a molecular glue initiating the degradation of neosubstrate HDAC1/2-CoREST-LSD1 through a multiprotein complex formed with KBTBD4, was carried out using the cryo-EM structure of its KBTBD4-HDAC2 complex. Structural modifications resulted in a 20-fold improvement in glue activity, demonstrated by the stability of its ternary complex with KBTBD4-HDAC2. These improvements were also accompanied by a robust degradation of LSD1 and the CoREST1 protein. Our results, although promising, also highlight the complexity of structure-guided glue design. The effect of the developed glues on the viability of HepG2 cells revealed a varying level of toxicity, which was disconnected from the glue activity. These observations highlight the potential impact of off-target effects on the biological activity of these glues.

Indexed as

Histone Deacetylase 1Histone Deacetylase 2Cell SurvivalCo-Repressor ProteinsCryoelectron MicroscopyHep G2 CellsHistone DemethylasesHumansMolecular StructureNerve Tissue ProteinsStructure-Activity RelationshipCo-Repressor ProteinsHDAC1 protein, humanHDAC2 protein, humanHistone Deacetylase 1Histone Deacetylase 2Histone DemethylasesKDM1A protein, humanNerve Tissue ProteinsKBTBD4molecular glueprotein degradationstructure based designtoxicity

Identifiers

PMID42642754
PMCPMC13506672

What Socratic holds

Textmetadata
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 Socratic graph.