Evidence map›Paper›PMID 42336816›Full record

ArticleNature communications2026

Structural basis for selective and potent degradation of IRAK4 by KT-474.

Xue Fei, Anand Ramanathan, Caroline A Daigle, Melissa Ford, Veronica Campbell, Xiaozhang Zheng, Mike Sintchak, Haoran Li, Hari Kamadurai, Richard Miller and 5 more

Abstract read
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In one paragraph

Article in Nature communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0citing papers in PubMed
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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

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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

15 authors.

Xue Fei *Kymera Therapeutics, Inc., Watertown, MA, USA.
Anand Ramanathan *Kymera Therapeutics, Inc., Watertown, MA, USA.
Caroline A DaigleKymera Therapeutics, Inc., Watertown, MA, USA.ORCID http://orcid.org/0000-0003-4888-9948
Melissa FordKymera Therapeutics, Inc., Watertown, MA, USA.
Veronica CampbellKymera Therapeutics, Inc., Watertown, MA, USA.
Xiaozhang ZhengKymera Therapeutics, Inc., Watertown, MA, USA.
Mike SintchakKymera Therapeutics, Inc., Watertown, MA, USA.
Haoran LiKymera Therapeutics, Inc., Watertown, MA, USA.
Hari KamaduraiKymera Therapeutics, Inc., Watertown, MA, USA.
Richard MillerKymera Therapeutics, Inc., Watertown, MA, USA.
Steven KazmirskiKymera Therapeutics, Inc., Watertown, MA, USA.
Xin HuangKymera Therapeutics, Inc., Watertown, MA, USA.
Matthew M WeissKymera Therapeutics, Inc., Watertown, MA, USA.ORCID http://orcid.org/0000-0002-2559-2183
Nello MainolfiKymera Therapeutics, Inc., Watertown, MA, USA.
Xiao ZhuKymera Therapeutics, Inc., Watertown, MA, USA. szhu@kymeratx.com.ORCID http://orcid.org/0000-0001-7647-4390

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Targeted protein degradation has emerged as a promising drug modality, with potential applications across many immuno-inflammatory diseases. KT-474 is an orally bioavailable interleukin-1 receptor-associated kinase 4 (IRAK4) heterobifunctional degrader evaluated in clinical trials for atopic dermatitis and hidradenitis suppurativa. Here we present structural, biophysical, and computational characterization of an IRAK4:KT-474:CRBN/DDB1 complex. Cryo-EM structure of the complex reveals a unique and non-native protein-protein interaction (PPI) surface mediated by a network of polar and apolar contacts, including key hydrophobic engagements mediated by CRBN Phe150. This complex exhibits negative cooperativity, arising from an interplay between weakly favorable PPI and conformational flexibility of the degrader. Moreover, the structure provides insight into the selective degradation profile of KT-474. Our results offer important insights into the mechanism of action of KT-474 and highlight the value of cryo-EM structures in the optimization of protein degraders.

Indexed as

Interleukin-1 Receptor-Associated KinasesCryoelectron MicroscopyHumansModels, MolecularProtein BindingProtein ConformationProteolysisUbiquitin-Protein LigasesInterleukin-1 Receptor-Associated KinasesIRAK4 protein, humanUbiquitin-Protein Ligases

Identifiers

PMID42336816
PMCPMC13443748

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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.