Design, synthesis, and bioevaluation of SOS1 PROTACs derived from pyrido[2,3-d]pyrimidin-7-one-based SOS1 inhibitor.

Anti-cancer activity KRAS mutation PROTAC SOS1

Journal

Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377

Informations de publication

Date de publication:
05 May 2024
Historique:
received: 11 03 2024
revised: 27 04 2024
accepted: 04 05 2024
medline: 8 5 2024
pubmed: 8 5 2024
entrez: 7 5 2024
Statut: aheadofprint

Résumé

Oncogenic KRAS mutations drive an approximately 25 % of all human cancers. Son of Sevenless 1 (SOS1), a critical guanine nucleotide exchange factor, catalyzes the activation of KRAS. Targeting SOS1 degradation has engaged as a promising therapeutic strategy for KRAS-mutant cancers. Herein, we designed and synthesized a series of novel CRBN-recruiting SOS1 PROTACs using the pyrido[2,3-d]pyrimidin-7-one-based SOS1 inhibitor as the warhead. One representative compound 11o effectively induced the degradation of SOS1 in three different KRAS-mutant cancer cell lines with DC

Identifiants

DOI: 10.1016/j.bmcl.2024.129780 PMID: 38714262
pubmed: 38714262
pii: S0960-894X(24)00182-3
doi: 10.1016/j.bmcl.2024.129780
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

129780

Informations de copyright

Copyright © 2024. Published by Elsevier Ltd.

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

Kun Wang (K)

School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.

Zehui Zhou (Z)

Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.

Xinyi Ma (X)

School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.

Jiahang Xu (J)

School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; University of Chinese Academy of Sciences, Beijing 100049, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.

Wangyang Xu (W)

School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.

Guizhen Zhou (G)

Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.

Chuan Zhou (C)

Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.

Huajie Li (H)

Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.

Mingyue Zheng (M)

School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; University of Chinese Academy of Sciences, Beijing 100049, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.

Sulin Zhang (S)

University of Chinese Academy of Sciences, Beijing 100049, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: slzhang@simm.ac.cn.

Tianfeng Xu (T)

School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: tfxu@simm.ac.cn.

Classifications MeSH