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Updated: Oct 1, 2025

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Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS

Chuan Zhou1, Zisheng Fan2,3, Zehui Zhou1,4

  • 1Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.

Journal of Medicinal Chemistry
|March 1, 2022
PubMed

Insights

Researchers developed novel SOS1 PROTACs for targeted cancer therapy. The best compound, 9d, effectively degraded SOS1 and inhibited KRAS-driven cancer cell proliferation and tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Targeting SOS1 is a promising strategy for pan-KRAS therapies.
  • SOS1 inhibitors show anticancer potential, with BI 1701963 in clinical trials.
  • SOS1 agonists offer new therapeutic avenues, but mechanisms require further study.

Purpose of the Study:

  • To discover the first SOS1 Proteolysis Targeting Chimeras (PROTACs).
  • To validate the use of agonists in designing PROTACs for SOS1 degradation.
  • To assess the therapeutic potential of SOS1 degradation in KRAS-driven cancers.

Main Methods:

  • Design and synthesis of novel SOS1 PROTACs by conjugating a VHL ligand to a known SOS1 agonist.
  • Evaluation of compound-induced SOS1 degradation in KRAS-driven cancer cell lines.
  • Assessment of antiproliferation activity and in vivo antitumor efficacy using tumor xenograft models.

Main Results:

  • The best PROTAC compound, 9d, successfully induced SOS1 degradation in various cancer cells.
  • Compound 9d exhibited superior antiproliferation activity compared to the parent agonist.
  • A xenograft study demonstrated significant antitumor potency of 9d against human lung cancer.

Conclusions:

  • Agonists can be effectively utilized to design SOS1 PROTACs.
  • Targeted degradation of SOS1 is a viable therapeutic strategy for KRAS-driven cancers.
  • SOS1 PROTACs represent a promising new class of anticancer agents.

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