Discovery of CNS Penetrant SOS1 Inhibitors for the Treatment of KRAS-Dependent Cancers

Son of Sevenless Homologue 1 (SOS1) is a promising oncology target with inhibitors in phase 1/2 clinical studies. A focused HTS triage led to a singular SOS1 series having a pyridyl core. The conformational preference of the diamide pyridyl core was critical to binding potency, leading to pyrazine and pyridyl being the preferred motifs. Application of structure-based design to build into a buried lipophilic pocket led to a significant 50-fold potency enhancement. Strategic fluorination of aryl rings and substituents generated compounds with favorable dipoles, low P-gp and BCRP efflux, and high rat Kp u,u . Multiple analogues were progressed into in vivo PK/PD studies where they were combined with a KRAS G12C inhibitor. Combination treated tumors in mice showed deeper, more sustained reductions in DUSP6 mRNA and phosphorylated ERK compared to KRAS G12C inhibitor alone. Thus, these novel CNS penetrant SOS1 inhibitors have potential to enhance antitumor responses when combined with RAS or MAPK inhibitors.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2026-06-16
DOI
https://doi.org/10.1021/acs.jmedchem.5c03800
Primary Topic
Protein Tyrosine Phosphatases
Type
article
Field-Weighted Citation Impact
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article

Discovery of CNS Penetrant SOS1 Inhibitors for the Treatment of KRAS-Dependent Cancers

Michael S. Bodnarchuk, Doyle J. Cassar, Anna D. Staniszewska, Samuel Nash et al.
Journal of Medicinal Chemistry
Protein Tyrosine Phosphatases
article

Discovery of CNS Penetrant SOS1 Inhibitors for the Treatment of KRAS-Dependent Cancers

Michael S. Bodnarchuk, Doyle J. Cassar, Anna D. Staniszewska, Samuel Nash, Sharan K. Bagal, Jason G. Kettle, Elsa Irving, Markus Schade, Gregory W. Kauffman, Gavin W. Collie, Christopher J. Stubbs, J. Breed, Alison Peter, Sandra Stefanovic-Barrett, Aaron Smith, Abhishek Srivastava, Coura R. N. Diène, Sean Gray, Sarah Northall, Lucy Young, Craig Hughes
article en

Abstract

Son of Sevenless Homologue 1 (SOS1) is a promising oncology target with inhibitors in phase 1/2 clinical studies. A focused HTS triage led to a singular SOS1 series having a pyridyl core. The conformational preference of the diamide pyridyl core was critical to binding potency, leading to pyrazine and pyridyl being the preferred motifs. Application of structure-based design to build into a buried lipophilic pocket led to a significant 50-fold potency enhancement. Strategic fluorination of aryl rings and substituents generated compounds with favorable dipoles, low P-gp and BCRP efflux, and high rat Kp u,u . Multiple analogues were progressed into in vivo PK/PD studies where they were combined with a KRAS G12C inhibitor. Combination treated tumors in mice showed deeper, more sustained reductions in DUSP6 mRNA and phosphorylated ERK compared to KRAS G12C inhibitor alone. Thus, these novel CNS penetrant SOS1 inhibitors have potential to enhance antitumor responses when combined with RAS or MAPK inhibitors.

Journal of Medicinal Chemistry
Target (United States) (US), Cancer Targeted Technology (United States) (US), AstraZeneca (Singapore) (SG)
Good health and well-being
Openalex Percentile: Top 12%
Protein Tyrosine Phosphatases
DOISourceOpenAlex
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