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Focused Structure-Based Virtual Screening Identifies Novel Inhibitors of SOS1
Silvia Bonomo1, Floriane Gibault1, Sharan K Bagal2
1Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
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.
Insights
Researchers identified novel compounds that inhibit SOS1, a key regulator of KRAS. This finding offers a new strategy for targeting abnormal KRAS activation in cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- KRAS activation is regulated by SOS1, which catalyzes GTP-to-GDP turnover.
- Abnormal KRAS activation drives several types of cancer.
- Inhibiting the SOS1::KRAS interaction is a promising anti-cancer strategy.
Purpose of the Study:
- To identify novel inhibitors of SOS1.
- To develop binders of SOS1 into functional inhibitors.
Main Methods:
- Virtual screening of the AstraZeneca compound collection.
- Identification of compounds with Heavy Atom Count between 21 and 26.
- Structure- and knowledge-based drug design.
Main Results:
- Two novel and efficient binders of SOS1 were identified.
- These binders met the minimal pharmacophoric requirements of known compounds.
- The binders were developed into functional SOS1 inhibitors.
Conclusions:
- Novel SOS1 inhibitors were discovered through virtual screening.
- These inhibitors represent a potential therapeutic strategy for KRAS-driven malignancies.
- Further development holds promise for cancer treatment.
