View in EDS

Developmental toxicology profile of the IRAK4 degrader KT-474.

Saved in:
Bibliographic Details
Title: Developmental toxicology profile of the IRAK4 degrader KT-474.
Authors: Enerson, Bradley E1 (AUTHOR), Cappon, Gregg2 (AUTHOR), Shi, Yatao1 (AUTHOR), Walther, Dirk M1 (AUTHOR), Campbell, Veronica1 (AUTHOR), Chen, Dapeng1 (AUTHOR), Kuhn, Eric1 (AUTHOR), Massa, Virginia1 (AUTHOR), Ho, Chris1 (AUTHOR), Zheng, Xiaozhang1 (AUTHOR)
Source: Toxicological Sciences. Feb2026, Vol. 209 Issue 2, p1-16. 16p.
Subjects: Developmental toxicology, Teratogenicity testing, Fetal development, Proteomics, Ubiquitin ligases, Proteolysis
Abstract: KT-474 is a first-in-class IRAK4 heterobifunctional degrader that utilizes cereblon (CRBN) for E3 ligase recruitment and was rationally designed to be devoid of immunomodulatory imide drug (IMiD)-related neosubstrate degradation. Like KT-474, most degraders in clinical trials to date rely on CRBN for E3 ligase recruitment to harness the ubiquitin-proteasome system to selectively degrade disease-associated proteins. Structural similarities of the CRBN-binding portion of these degraders to IMiDs (e.g. thalidomide) have raised safety concerns due to potential degradation of CRBN neosubstrates implicated in teratogenicity, such as SALL4. To address this theoretical concern, the potential of KT-474 to degrade CRBN neosubstrates in vitro and cause developmental toxicity in vivo was evaluated. Proteomic analyses across 3 human cell systems (peripheral blood mononuclear cells [PBMCs], induced pluripotent stem cells, and SK-N-DZ cells) demonstrated that KT-474 selectively degraded IRAK4 without affecting SALL4 or other detected CRBN neosubstrates. In embryo-fetal development studies, no KT-474-related malformations or embryo-fetal toxicity were observed in rats or rabbits at the highest doses tested. Associated exposures (AUC) provided 23- to 9-fold multiples, respectively, over exposures at the clinical dose of KT-474 associated with robust degradation of IRAK4 and early signals of efficacy. Deep IRAK4 degradation by KT-474 in primary rat cells, rabbit PBMCs, and a range of tissues provides confidence in the appropriateness of the animal species tested. Taken together, these data clearly differentiate KT-474 from IMiDs, support that CRBN-mediated teratogenicity seen with IMiD drugs is neosubstrate-driven, and demonstrate that structure-based design can generate highly selective degraders devoid of teratogenic risk. [ABSTRACT FROM AUTHOR]
Copyright of Toxicological Sciences is the property of Oxford University Press / USA and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
FullText Text:
  Availability: 0
Header DbId: egs
DbLabel: Engineering Source
An: 191979212
AccessLevel: 6
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 0
IllustrationInfo
Items – Name: Title
  Label: Title
  Group: Ti
  Data: Developmental toxicology profile of the IRAK4 degrader KT-474.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Enerson%2C+Bradley+E%22">Enerson, Bradley E</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Cappon%2C+Gregg%22">Cappon, Gregg</searchLink><relatesTo>2</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Shi%2C+Yatao%22">Shi, Yatao</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Walther%2C+Dirk+M%22">Walther, Dirk M</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Campbell%2C+Veronica%22">Campbell, Veronica</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Chen%2C+Dapeng%22">Chen, Dapeng</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kuhn%2C+Eric%22">Kuhn, Eric</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Massa%2C+Virginia%22">Massa, Virginia</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ho%2C+Chris%22">Ho, Chris</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zheng%2C+Xiaozhang%22">Zheng, Xiaozhang</searchLink><relatesTo>1</relatesTo> (AUTHOR)
– Name: TitleSource
  Label: Source
  Group: Src
  Data: <searchLink fieldCode="JN" term="%22Toxicological+Sciences%22">Toxicological Sciences</searchLink>. Feb2026, Vol. 209 Issue 2, p1-16. 16p.
– Name: Subject
  Label: Subjects
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Developmental+toxicology%22">Developmental toxicology</searchLink><br /><searchLink fieldCode="DE" term="%22Teratogenicity+testing%22">Teratogenicity testing</searchLink><br /><searchLink fieldCode="DE" term="%22Fetal+development%22">Fetal development</searchLink><br /><searchLink fieldCode="DE" term="%22Proteomics%22">Proteomics</searchLink><br /><searchLink fieldCode="DE" term="%22Ubiquitin+ligases%22">Ubiquitin ligases</searchLink><br /><searchLink fieldCode="DE" term="%22Proteolysis%22">Proteolysis</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: KT-474 is a first-in-class IRAK4 heterobifunctional degrader that utilizes cereblon (CRBN) for E3 ligase recruitment and was rationally designed to be devoid of immunomodulatory imide drug (IMiD)-related neosubstrate degradation. Like KT-474, most degraders in clinical trials to date rely on CRBN for E3 ligase recruitment to harness the ubiquitin-proteasome system to selectively degrade disease-associated proteins. Structural similarities of the CRBN-binding portion of these degraders to IMiDs (e.g. thalidomide) have raised safety concerns due to potential degradation of CRBN neosubstrates implicated in teratogenicity, such as SALL4. To address this theoretical concern, the potential of KT-474 to degrade CRBN neosubstrates in vitro and cause developmental toxicity in vivo was evaluated. Proteomic analyses across 3 human cell systems (peripheral blood mononuclear cells [PBMCs], induced pluripotent stem cells, and SK-N-DZ cells) demonstrated that KT-474 selectively degraded IRAK4 without affecting SALL4 or other detected CRBN neosubstrates. In embryo-fetal development studies, no KT-474-related malformations or embryo-fetal toxicity were observed in rats or rabbits at the highest doses tested. Associated exposures (AUC) provided 23- to 9-fold multiples, respectively, over exposures at the clinical dose of KT-474 associated with robust degradation of IRAK4 and early signals of efficacy. Deep IRAK4 degradation by KT-474 in primary rat cells, rabbit PBMCs, and a range of tissues provides confidence in the appropriateness of the animal species tested. Taken together, these data clearly differentiate KT-474 from IMiDs, support that CRBN-mediated teratogenicity seen with IMiD drugs is neosubstrate-driven, and demonstrate that structure-based design can generate highly selective degraders devoid of teratogenic risk. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Toxicological Sciences is the property of Oxford University Press / USA and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=egs&AN=191979212
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1093/toxsci/kfaf170
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 16
        StartPage: 1
    Subjects:
      – SubjectFull: Developmental toxicology
        Type: general
      – SubjectFull: Teratogenicity testing
        Type: general
      – SubjectFull: Fetal development
        Type: general
      – SubjectFull: Proteomics
        Type: general
      – SubjectFull: Ubiquitin ligases
        Type: general
      – SubjectFull: Proteolysis
        Type: general
    Titles:
      – TitleFull: Developmental toxicology profile of the IRAK4 degrader KT-474.
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Enerson, Bradley E
      – PersonEntity:
          Name:
            NameFull: Cappon, Gregg
      – PersonEntity:
          Name:
            NameFull: Shi, Yatao
      – PersonEntity:
          Name:
            NameFull: Walther, Dirk M
      – PersonEntity:
          Name:
            NameFull: Campbell, Veronica
      – PersonEntity:
          Name:
            NameFull: Chen, Dapeng
      – PersonEntity:
          Name:
            NameFull: Kuhn, Eric
      – PersonEntity:
          Name:
            NameFull: Massa, Virginia
      – PersonEntity:
          Name:
            NameFull: Ho, Chris
      – PersonEntity:
          Name:
            NameFull: Zheng, Xiaozhang
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 01
              M: 02
              Text: Feb2026
              Type: published
              Y: 2026
          Identifiers:
            – Type: issn-print
              Value: 10966080
          Numbering:
            – Type: volume
              Value: 209
            – Type: issue
              Value: 2
          Titles:
            – TitleFull: Toxicological Sciences
              Type: main
ResultId 1