Design and structural optimization of novel SOS1 inhibitors in KRAS-driven cancers

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Targeting SOS1, a guanine nucleotide exchange factor, is a promising strategy for KRAS-driven cancers.
• Increasing drug resistance necessitates the development of novel SOS1 inhibitors due to structural similarities in existing analogs.

Purpose of the Study:

• To discover and characterize a new SOS1 inhibitor with improved properties for treating KRAS-driven cancers.
• To evaluate the preclinical efficacy and solubility of a novel para-dimethylaminoazetidine quinazoline scaffold inhibitor.

Main Methods:

• Synthesis of novel SOS1 inhibitors utilizing a para-dimethylaminoazetidine quinazoline scaffold.
• In vitro assays including KRASG12C::SOS1 protein-protein interaction (PPI) inhibition and 3D cancer cell proliferation assays.
• Assessment of aqueous solubility at physiological pH and Western blot analysis for downstream signaling markers (p-ERK, p-AKT) in NCI-H358 cells.

Main Results:

• Compound 10i, featuring the novel scaffold, exhibited superior activity compared to the known SOS1 inhibitor Hit 1 in PPI and proliferation assays.
• Compound 10i demonstrated enhanced aqueous solubility at pH 6.8.
• Treatment with compound 10i led to the downregulation of phosphorylated ERK and AKT in NCI-H358 cancer cells.

Conclusions:

• Compound 10i represents a promising drug candidate for KRAS-driven cancers.
• The novel scaffold and improved properties of compound 10i offer a potential solution to overcome existing drug resistance.
• Further investigation into compound 10i is warranted for its clinical development in oncology.