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

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• Son of Sevenless Homologue 1 (SOS1) is a key signaling protein and a promising target in oncology.
• Existing inhibitors are in early-phase clinical trials, highlighting the need for novel therapeutic strategies.

Purpose of the Study:

• To develop novel, CNS-penetrant SOS1 inhibitors with enhanced potency and favorable pharmacokinetic properties.
• To evaluate the efficacy of these SOS1 inhibitors in combination with a KRAS inhibitor in preclinical cancer models.

Main Methods:

• Structure-based drug design and high-throughput screening (HTS) were employed to identify and optimize SOS1 inhibitors.
• Lead compounds underwent medicinal chemistry optimization, including strategic fluorination and exploration of core motifs (pyrazine, pyridyl).
• In vivo pharmacokinetic/pharmacodynamic (PK/PD) studies were conducted in combination with a KRAS^G12C inhibitor.

Main Results:

• A singular SOS1 inhibitor series with a pyridyl core was identified, with conformational preference being critical for potency.
• Structure-based design led to a 50-fold enhancement in binding potency by targeting a lipophilic pocket.
• Optimized compounds exhibited favorable properties, including low efflux (P-gp, BCRP) and high brain penetration (rat Kp_u,u).
• Combination therapy in mice resulted in deeper and more sustained reductions in DUSP6 mRNA and phosphorylated ERK compared to monotherapy.

Conclusions:

• Novel CNS-penetrant SOS1 inhibitors were successfully developed with significant potency and improved drug-like properties.
• Combination of these SOS1 inhibitors with a KRAS^G12C inhibitor demonstrated enhanced antitumor activity in vivo.
• These findings suggest that SOS1 inhibitors hold promise for improving therapeutic responses in combination with RAS or MAPK pathway inhibitors.