Cereblon-based Bifunctional Degrader of SOS1, BTX-6654, Targets Multiple KRAS Mutations and Inhibits Tumor Growth

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• KRAS mutations are key drivers in approximately 25% of human cancers.
• Current KRAS G12C inhibitors face acquired resistance due to pathway reactivation.
• Son of sevenless homolog 1 (SOS1) is a critical upstream activator of KRAS and a potential therapeutic target.

Purpose of the Study:

• To develop novel SOS1 degraders as a pan-KRAS therapeutic strategy.
• To evaluate the efficacy of SOS1 degraders in circumventing resistance mechanisms.
• To establish preclinical proof of concept for SOS1 degraders in KRAS-driven cancers.

Main Methods:

• Development of cereblon-based bifunctional SOS1 degraders (BTX-6654 and BTX-7312).
• Assessment of target-specific SOS1 degradation and downstream signaling inhibition (pERK, pS6).
• Evaluation of antiproliferative activity in various KRAS-mutant cell lines and xenograft models.

Main Results:

• BTX-6654 and BTX-7312 demonstrated potent and specific SOS1 degradation.
• Compounds reduced downstream signaling markers and inhibited proliferation in KRAS-mutant cells.
• BTX-6654 showed dose-dependent SOS1 degradation and tumor growth inhibition in xenografts, with synergistic effects when combined with KRAS and MEK inhibitors.

Conclusions:

• Cereblon-based bifunctional SOS1 degraders represent a promising new therapeutic modality for KRAS-driven cancers.
• These degraders show potential for single-agent and combination therapy, possibly overcoming resistance mechanisms.
• BTX-6654 provides preclinical validation for targeting SOS1 degradation in oncology.