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Updated: Jul 16, 2025

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans
08:12

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

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Discovery of novel indazole derivatives as SOS1 agonists that activate KRAS signaling

Lu Liu1, Zhendong Song1, Guangjin Fan1

  • 1Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, 510006 Guangzhou, Guangdong, PR China.

Bioorganic & Medicinal Chemistry
|September 9, 2023
PubMed

Insights

Researchers discovered novel small-molecule SOS1 agonists using an indazole scaffold. Compound 11 activates SOS1, enhancing cellular RAS-GTP levels and modulating ERK1/2 phosphorylation, showing therapeutic potential for RAS signaling modulation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • KRAS mutations are crucial in tumor pathogenesis, but targeting KRAS remains challenging due to resistance and mutation diversity.
  • Modulating KRAS function by interfering with KRAS-SOS1 interactions presents a promising therapeutic strategy.

Purpose of the Study:

  • To discover novel small-molecule SOS1 agonists.
  • To investigate the therapeutic potential of activating SOS1 for modulating RAS signaling.

Main Methods:

  • Structure-based drug design and optimization of a novel indazole scaffold.
  • In vitro assays to determine SOS1 activation potency (p-ERK EC50).
  • Cellular assays in HeLa cells to measure RAS-GTP levels and ERK1/2 phosphorylation.

Main Results:

  • Identification of compound 11, a potent SOS1 activator with an EC50 of 1.53 μM.
  • Compound 11 enhances cellular RAS-GTP levels.
  • Compound 11 demonstrates biphasic modulation of ERK1/2 phosphorylation via an on-target mechanism.

Conclusions:

  • Novel indazole-based small molecules effectively activate SOS1.
  • Compound 11 shows therapeutic potential for modulating RAS signaling by activating SOS1, offering a new avenue for cancer therapy.
Keywords:
AgonistAnti-tumorIndazoleKRASSOS1

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