Discovery of LHF418 as a new potent SOS1 PROTAC degrader.

Antitumor Degrader KRAS PROTAC SOS1

Journal

Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298

Informations de publication

Date de publication:
02 Mar 2024
Historique:
received: 20 12 2023
revised: 26 02 2024
accepted: 27 02 2024
medline: 16 3 2024
pubmed: 16 3 2024
entrez: 15 3 2024
Statut: aheadofprint

Résumé

Son of sevenless homolog 1 (SOS1) plays a pivotal role as a molecular switch in the conversion of GDP-bound inactive KRAS to its active GTP-bound form, making SOS1 a promising therapeutic target for KRAS-driven cancers. While the most advanced SOS1 inhibitor has processed to phase I clinical trial, the exploration of novel SOS1 targeting strategies with distinct modes of action remains required. By employing proteolysis targeting chimera (PROTAC) technology, we obtained a series of new SOS1 degraders. The representative compound LHF418 potently induced SOS1 degradation with a DC

Identifiants

DOI: 10.1016/j.bmc.2024.117661 PMID: 38489998
pubmed: 38489998
pii: S0968-0896(24)00075-0
doi: 10.1016/j.bmc.2024.117661
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

117661

Informations de copyright

Copyright © 2024 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Auteurs

Huifan Li (H)

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.

Minxue Chai (M)

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based Materials, College of Chemistry and Materials Science, Anhui Normal University, Wuhu 241000, China.

Yihan Chen (Y)

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.

Fengtao Zhou (F)

International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, Guangzhou 511400, China.

Xiaomei Ren (X)

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.

Jian Xu (J)

Livzon Research Institute, Livzon Pharmaceutical Group Inc., Zhuhai 519000, China.

Jian Wang (J)

Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based Materials, College of Chemistry and Materials Science, Anhui Normal University, Wuhu 241000, China. Electronic address: wang_jian989@163.com.

Zhen Wang (Z)

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; Ningbo Zhongke Creation Center of New Materials, Ningbo 315000, China. Electronic address: wangz@sioc.ac.cn.

Weixue Huang (W)

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; Ningbo Zhongke Creation Center of New Materials, Ningbo 315000, China. Electronic address: wxhuang@sioc.ac.cn.

Classifications MeSH