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An overview of PROTACs targeting KRAS and SOS1 as antitumor agents

Zhiqiu Han1, Qianping Wu1, Hongxin Rao1

  • 1School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, 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, 19 Yuquan Road, Beijing 100049, China.

Bioorganic & Medicinal Chemistry Letters
|May 17, 2025
PubMed

Insights

Targeting KRAS and SOS1 with PROTACs offers a new strategy for treating KRAS-driven cancers. This approach aims to overcome resistance to existing therapies and address mutations like G12D and G12V.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • KRAS mutations drive ~25% of human cancers, making it a key oncogene.
  • Son of Sevenless 1 (SOS1) is crucial in KRAS signaling and a target for pan-KRAS inhibition.
  • Current KRAS G12C inhibitors face resistance and do not address other KRAS mutations (G12D, G12V).

Purpose of the Study:

  • To review Proteolysis Targeting Chimeras (PROTACs) designed for KRAS and SOS1 degradation.
  • To explore chemical structures, design strategies, and structure-activity relationships (SAR) of these PROTACs.
  • To summarize in vitro and in vivo activities of PROTACs targeting KRAS and SOS1.

Main Methods:

  • Literature review of PROTACs targeting KRAS and SOS1.
  • Analysis of chemical structures and SAR studies.
  • Evaluation of in vitro and in vivo experimental data for PROTAC efficacy.

Main Results:

  • PROTAC-mediated degradation of KRAS and SOS1 is a rapidly advancing strategy.
  • Approved KRAS G12C inhibitors show limitations due to resistance and mutation specificity.
  • PROTACs offer a potential solution for overcoming resistance and targeting broader KRAS mutations.

Conclusions:

  • PROTACs degrading KRAS and SOS1 represent a promising therapeutic strategy for KRAS-driven cancers.
  • Further development is needed to accelerate the clinical application of these novel chemotherapies.
  • Addressing challenges and exploring opportunities in PROTAC design is crucial for future advancements.
Keywords:
Antitumor agentKRASPROTACSOS1

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