Nonclinical teratogenicity safety assessment of CRBN-engaging targeted protein degraders: Points to consider

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology Pub Date : 2025-02-25 DOI:10.1016/j.yrtph.2025.105793

Lise I. Loberg , William R. Proctor , Andrew D. Burdick , Annick Cauvin , Anthony M. DeLise , Michelle Hemkens , Andreas M. Hohlbaum , Renee Hukkanen , Alanna E. Sedgwick , Dana Shuey , Doris T. Zane , Katie Stamp

{"title":"Nonclinical teratogenicity safety assessment of CRBN-engaging targeted protein degraders: Points to consider","authors":"Lise I. Loberg , William R. Proctor , Andrew D. Burdick , Annick Cauvin , Anthony M. DeLise , Michelle Hemkens , Andreas M. Hohlbaum , Renee Hukkanen , Alanna E. Sedgwick , Dana Shuey , Doris T. Zane , Katie Stamp","doi":"10.1016/j.yrtph.2025.105793","DOIUrl":null,"url":null,"abstract":"<div><div>Targeted protein degraders (or degraders) are an emerging small molecule drug modality with transformative therapeutic potential. Currently, most degraders are developed for severe life-threatening disorders and engage the E3 ligase cereblon. One barrier to the broader use of degraders is the potential risk of embryofetal toxicity with cereblon-engaging degraders, exemplified by thalidomide. Thalidomide (and analogs, known as immunomodulatory drugs) binds cereblon and modifies its substrate repertoire, leading to degradation of intended and multiple unintended neosubstrates. Some cereblon-engaging degraders have been engineered to avoid the degradation of unintended neosubstrates implicated in teratogenicity, specifically SALL4. Mechanistic links between SALL4 degradation by thalidomide and human teratogenicity have been established; further, SALL4 degradation by thalidomide (and its analogs) has been linked to teratogenicity in susceptible nonclinical species. It is generally accepted that SALL4 degradation is unlikely to be the only mechanism of teratogenicity associated with thalidomide and its analogs. Currently, best practices to evaluate the teratogenicity risk of cereblon-engaging degraders have not been established. Here, we present points to consider in the teratogenicity safety assessment of cereblon-engaging degraders from the perspective of an IQ consortium working group.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"158 ","pages":"Article 105793"},"PeriodicalIF":3.0000,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Regulatory Toxicology and Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0273230025000236","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, LEGAL","Score":null,"Total":0}

引用次数: 0

Abstract

Targeted protein degraders (or degraders) are an emerging small molecule drug modality with transformative therapeutic potential. Currently, most degraders are developed for severe life-threatening disorders and engage the E3 ligase cereblon. One barrier to the broader use of degraders is the potential risk of embryofetal toxicity with cereblon-engaging degraders, exemplified by thalidomide. Thalidomide (and analogs, known as immunomodulatory drugs) binds cereblon and modifies its substrate repertoire, leading to degradation of intended and multiple unintended neosubstrates. Some cereblon-engaging degraders have been engineered to avoid the degradation of unintended neosubstrates implicated in teratogenicity, specifically SALL4. Mechanistic links between SALL4 degradation by thalidomide and human teratogenicity have been established; further, SALL4 degradation by thalidomide (and its analogs) has been linked to teratogenicity in susceptible nonclinical species. It is generally accepted that SALL4 degradation is unlikely to be the only mechanism of teratogenicity associated with thalidomide and its analogs. Currently, best practices to evaluate the teratogenicity risk of cereblon-engaging degraders have not been established. Here, we present points to consider in the teratogenicity safety assessment of cereblon-engaging degraders from the perspective of an IQ consortium working group.

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

来源期刊

Regulatory Toxicology and Pharmacology 医学-毒理学

CiteScore

6.70

自引率

8.80%

发文量

147

审稿时长

58 days

期刊介绍： Regulatory Toxicology and Pharmacology publishes peer reviewed articles that involve the generation, evaluation, and interpretation of experimental animal and human data that are of direct importance and relevance for regulatory authorities with respect to toxicological and pharmacological regulations in society. All peer-reviewed articles that are published should be devoted to improve the protection of human health and environment. Reviews and discussions are welcomed that address legal and/or regulatory decisions with respect to risk assessment and management of toxicological and pharmacological compounds on a scientific basis. It addresses an international readership of scientists, risk assessors and managers, and other professionals active in the field of human and environmental health. Types of peer-reviewed articles published: -Original research articles of relevance for regulatory aspects covering aspects including, but not limited to: 1.Factors influencing human sensitivity 2.Exposure science related to risk assessment 3.Alternative toxicological test methods 4.Frameworks for evaluation and integration of data in regulatory evaluations 5.Harmonization across regulatory agencies 6.Read-across methods and evaluations -Contemporary Reviews on policy related Research issues -Letters to the Editor -Guest Editorials (by Invitation)