Discovery of a first-in-class protein degrader for the c-ros oncogene 1 (ROS1)

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• ROS1 fusions are key drivers in non-small cell lung cancer (NSCLC).
• Current therapies inhibit ROS1 activity but do not eliminate the oncogenic driver.
• Protein degraders offer a more potent therapeutic strategy by eliminating target oncoproteins.

Purpose of the Study:

• To develop and characterize the first ROS1-specific PROteolysis-TArgeting Chimera (PROTAC).
• To evaluate the anti-tumour efficacy of the novel PROTAC against ROS1 fusion-driven NSCLC.
• To investigate the mechanism of action and pharmacokinetic profile of the PROTAC.

Main Methods:

• PROTAC design using molecular docking and rational drug design.
• In vitro studies in engineered cell lines (Ba/F3, HCC78) expressing ROS1 fusions.
• In vivo efficacy assessment using a mouse xenograft model.
• Mechanistic studies involving ubiquitination and proteasomal degradation pathways.

Main Results:

• SIAIS039 effectively degrades multiple ROS1 fusion oncoproteins (CD74-ROS1, SDC4-ROS1, SLC34A2-ROS1).
• SIAIS039 demonstrates significant anti-tumour activity, suppressing proliferation, inducing cell cycle arrest, and apoptosis.
• The PROTAC exhibits superior efficacy compared to approved drugs and matches top-tier inhibitors, with good oral bioavailability.

Conclusions:

• SIAIS039 represents a novel and potent therapeutic strategy for ROS1 fusion-positive NSCLC via targeted protein degradation.
• The study validates PROTAC technology as a promising approach for treating cancers driven by specific oncoproteins.
• This work lays the groundwork for developing next-generation PROTACs for ROS1-driven malignancies.