Targeting transcription factors through an IMiD independent zinc finger domain

Author:

Liu Bee Hui,Liu Miao,Radhakrishnan Sridhar,Jaladanki Chaitanya Kumar,Gao Chong,Tang Jing Ping,Kumari Kalpana,Go Mei Lin,Vu Kim Anh L.,Seo Hyuk-SooORCID,Song Kijun,Tian Xi,Feng Li,Tan Justin L.,Bassal Mahmoud A.,Arthanari Haribabu,Qi Jun,Dhe-Paganon Sirano,Fan Hao,Tenen Daniel G.ORCID,Chai Li

Abstract

AbstractImmunomodulatory imide drugs (IMiDs) degrade specific C2H2 zinc finger degrons in transcription factors, making them effective against certain cancers. SALL4, a cancer driver, contains seven C2H2 zinc fingers in four clusters, including an IMiD degron in zinc finger cluster two (ZFC2). Surprisingly, IMiDs do not inhibit growth of SALL4 expressing cancer cells. To overcome this limit, we focused on a non-IMiD degron, SALL4 zinc finger cluster four (ZFC4). By combining AlphaFold and the ZFC4-DNA crystal structure, we identified a potential ZFC4 drug pocket. Utilizing anin silicodocking algorithm and cell viability assays, we screened chemical libraries and discovered SH6, which selectively targets SALL4-expressing cancer cells. Mechanistic studies revealed that SH6 degrades SALL4 protein through the CUL4A/CRBN pathway, while deletion of ZFC4 abolished this activity. Moreover, SH6 led to significant 62% tumor growth inhibition of SALL4+ xenografts in vivo and demonstrated good bioavailability in pharmacokinetic studies. In summary, these studies represent a new approach for IMiD independent drug discovery targeting C2H2 transcription factors in cancer.Graphical Abstract

Publisher

Cold Spring Harbor Laboratory

Reference56 articles.

1. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Identifier NTC03888612. Trial of ARV-110 in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC); 2019 Mar. Available from: https://clinicaltrials.gov/ct2/show/NCT03888612.

2. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Identifier NTC04072952. A Phase 1/2 Trial of ARV-471 Alone and in Combination With Palbociclib (IBRANCE®) in Patients With ER+/HER2-Locally Advanced or Metastatic Breast Cancer (mBC); 2019 Aug. Available from: https://clinicaltrials.gov/ct2/show/NCT04072952.

3. PHENIX: a comprehensive Python-based system for macromolecular structure solution

4. Improved prediction of protein-protein interactions using AlphaFold2;Nat Commun,2022

5. Targeting transcription factors in cancer - from undruggable to reality;Nat Rev Cancer,2019

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3