Focused Structure-Based Virtual Screening Identifies Novel Inhibitors of SOS1

SOS1 is one of the key regulators of KRAS where it catalyzes the GTP-to-GDP turnover required for KRAS activation. Inhibition of the SOS1::KRAS interaction is an attractive strategy to modulate abnormal KRAS activation, which is responsible for several malignancies. In this work, we performed a virtual screening campaign on the AstraZeneca compound collection with Heavy Atom Count between 21 and 26 and identified two novel and efficient binders of SOS1 which fulfill the minimal pharmacophoric requirements disclosed in known compounds. Subsequently, structure- and knowledge-based approaches were applied to develop these binders into functional inhibitors of SOS1.

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Publication Details

Journal
ACS Medicinal Chemistry Letters
Published
2025-09-04
DOI
https://doi.org/10.1021/acsmedchemlett.5c00302
Citations
2
Primary Topic
Microbial Natural Products and Biosynthesis
Type
article
Field-Weighted Citation Impact
2.79
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article

Focused Structure-Based Virtual Screening Identifies Novel Inhibitors of SOS1

C. R. Diène, Paolo Di Fruscia, Craig D. Hughes, Floriane Gibault et al.
2 citations
ACS Medicinal Chemistry Letters
Microbial Natural Products and Biosynthesis
2.79
article

Focused Structure-Based Virtual Screening Identifies Novel Inhibitors of SOS1

C. R. Diène, Paolo Di Fruscia, Craig D. Hughes, Floriane Gibault, Michael Lainchbury, Sharan K. Bagal, Dhadchayini Jeyaharan, J. Henry Blackwell, Sarah Northall, Yunhua Chen, Jason G. Kettle, Alexander G. Milbradt, Honglin Hao, Maxime Couturier, Gavin W. Collie, Katherine B. Peters, Silvia Bonomo, Sean A. Gray, Christopher J. Stubbs, J. Breed, Elizabeth Underwood
article en
2 citations

Abstract

SOS1 is one of the key regulators of KRAS where it catalyzes the GTP-to-GDP turnover required for KRAS activation. Inhibition of the SOS1::KRAS interaction is an attractive strategy to modulate abnormal KRAS activation, which is responsible for several malignancies. In this work, we performed a virtual screening campaign on the AstraZeneca compound collection with Heavy Atom Count between 21 and 26 and identified two novel and efficient binders of SOS1 which fulfill the minimal pharmacophoric requirements disclosed in known compounds. Subsequently, structure- and knowledge-based approaches were applied to develop these binders into functional inhibitors of SOS1.

ACS Medicinal Chemistry LettersVol. 16(10)
AstraZeneca (United Kingdom) (GB), Target (United States) (US), Pharmaron (United Kingdom) (GB), AstraZeneca (Singapore) (SG), AstraZeneca (Germany) (DE)
Openalex Percentile: Top 9%
Microbial Natural Products and Biosynthesis
2.79
DOISourceOpenAlex
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