Discovery of Oral Degraders of the ROS1 Fusion Protein with Potent Activity against Secondary Resistance Mutations

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Therapeutic resistance to ROS1 inhibitors like crizotinib and lorlatinib limits long-term patient benefit.
• On-target mutations in the ROS1 kinase domain are a major cause of acquired resistance, with limited treatment options.
• Proteolytic degradation offers a potential strategy to overcome resistance by eliminating the target protein.

Purpose of the Study:

• To identify and characterize a novel therapeutic agent capable of inducing proteolytic degradation of ROS1.
• To evaluate the efficacy of this ROS1 degrader in preclinical models of ROS1-driven cancers, including those with resistance mutations.
• To assess the pharmacokinetic profile and anti-tumor activity of the identified ROS1 degrader.

Main Methods:

• Discovery and optimization of a potent, orally active small molecule targeting ROS1 for degradation.
• In vitro assessment of ROS1 degradation, inhibition of downstream signaling (phospho-ROS1), and anti-proliferative effects in cancer cell lines.
• In vivo evaluation of anti-tumor efficacy and pharmacokinetics in relevant preclinical cancer models.

Main Results:

• Identification of a potent, orally bioavailable ROS1 degrader with favorable pharmacokinetic properties.
• The degrader effectively inhibits ROS1-dependent cell proliferation and tumor growth by inducing ROS1 degradation and reducing phospho-ROS1 levels.
• The degradation-based approach demonstrated superior potency compared to inhibition and successfully overcame on-target mutation-mediated resistance to tyrosine kinase inhibitors.

Conclusions:

• Proteolytic degradation of ROS1 represents a promising therapeutic strategy for ROS1-driven malignancies.
• The identified ROS1 degrader is a potent anti-cancer agent capable of overcoming acquired resistance mechanisms.
• This novel degradation-based modality offers a potential new treatment option for patients with acquired resistance to existing ROS1 inhibitors.