Discovery of Orally Bioavailable SOS1 Inhibitors for Suppressing KRAS-Driven Carcinoma

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• The Son of Sevenless 1 (SOS1) and Kirsten rat sarcoma viral oncogene (KRAS) interaction is a key driver of proliferation and survival in various cancers.
• Previous research identified compound 40a, a tetracyclic quinazoline derivative, as an orally bioavailable SOS1 inhibitor.

Purpose of the Study:

• To discover and develop novel SOS1 inhibitors for the treatment of KRAS-driven tumors.
• To present compound 13c as a clinical drug candidate with improved properties over previous compounds.

Main Methods:

• Structure-based drug design and medicinal chemistry efforts led to the identification of compound 13c.
• Biochemical and cellular assays were used to determine the inhibitory potency of 13c against the SOS1-KRAS interaction (IC50 values).
• Pharmacokinetic studies in beagles and efficacy studies in Mia-paca-2 pancreas xenograft mouse models were conducted. In vitro studies assessed CYP3A4 inhibition and toxicological investigations evaluated cardiac safety.

Main Results:

• Compound 13c potently disrupted the SOS1-KRAS protein-protein interaction with IC50 values of 3.9 nM (biochemical) and 21 nM (cellular).
• 13c demonstrated a favorable pharmacokinetic profile, achieving 86.8% oral bioavailability in beagles and significant tumor suppression (83.0%) in preclinical models.
• Compared to BI-3406, 13c exhibited weaker time-dependent CYP3A4 inhibition, suggesting a reduced risk of drug-drug interactions, and a lower risk of sudden cardiac death.

Conclusions:

• Compound 13c is a promising clinical drug candidate for targeting KRAS-driven cancers.
• 13c offers potent inhibition of the SOS1-KRAS pathway with favorable pharmacokinetics and an improved safety profile.
• Further preclinical evaluation of 13c is ongoing, highlighting its potential in cancer therapy.