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Updated: Oct 5, 2025

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Targeting RAS oncogenesis with SOS1 inhibitors

Roman Christian Hillig1, Benjamin Bader2

  • 1Structural Biology, Lead Discovery, Nuvisan ICB GmbH, Berlin, Germany.

Advances in Cancer Research
|February 1, 2022
PubMed

Insights

Direct RAS inhibitors are limited, but SOS1 inhibitors show promise for cancer therapy. Combining SOS1 inhibitors with other treatments may overcome resistance in RAS-driven tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • RAS proteins are crucial in human cancers, but direct inhibitors are limited to KRAS G12C.
  • The RAS guanine nucleotide exchange factor, SOS1, is an alternative therapeutic target.
  • Significant advancements have been made in developing small molecule modulators of SOS1.

Purpose of the Study:

  • To review the discovery and development of small molecule SOS1 modulators.
  • To discuss their molecular binding modes and mechanisms of action.
  • To explore the potential of SOS1 inhibitors in combination therapies for RAS-driven cancers.

Main Methods:

  • Literature review of academic and industry research on SOS1 inhibitors.
  • Analysis of molecular binding modes and mechanisms of action.
  • Evaluation of combination strategies for RAS-driven tumors.

Main Results:

  • Progress in optimizing small molecule activators and inhibitors of SOS1.
  • Understanding of SOS1 modulators' binding and action.
  • Identification of potential combination partners for SOS1 inhibitors.

Conclusions:

  • SOS1 inhibitors represent a promising alternative for targeting RAS-driven cancers.
  • Combination therapies involving SOS1 inhibitors are likely essential to overcome resistance.
  • Further research is needed to determine optimal combination partners for patient benefit.
Keywords:
ActivatorCancerCombination therapyGEFGuanine nucleotide exchange factorKRASRASopathiesSOS1Small molecule inhibitorSon of sevenless

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