Fragment-Based Discovery of a Dual pan-RET/VEGFR2 Kinase Inhibitor Optimized for Single-Agent Polypharmacology

Area of Science:

• Oncology
• Pharmacology
• Medicinal Chemistry

Background:

• The rearranged during transfection (RET) tyrosine kinase is oncogenic and implicated in various cancers.
• Targeting RET is a key strategy in cancer therapy, but resistance and alternative pathways can limit efficacy.

Purpose of the Study:

• To identify and characterize a novel small molecule inhibitor targeting oncogenic RET.
• To evaluate the inhibitor's efficacy and safety profile, including its polypharmacology.

Main Methods:

• Fragment-based chemical screening to discover novel inhibitors.
• Biochemical assays, kinetic analysis, and molecular modeling to characterize inhibitor binding and mechanism.
• Cell-based assays and in vivo studies in mouse models to assess anti-tumor activity and toxicity.

Main Results:

• A novel type II RET inhibitor, Pz-1, was identified, binding the "DFG-out" conformation.
• Pz-1 demonstrated potent inhibition of RET oncoproteins and also targeted VEGFR2, impacting tumor vascularization.
• In vivo, Pz-1 abrogated tumor formation in RET-mutant models and reduced RET/VEGFR2 phosphorylation in tumors.
• No detectable toxicity was observed up to 100 mg/kg, suggesting a broad therapeutic window.

Conclusions:

• Pz-1 is a potent, dual-acting inhibitor of RET and VEGFR2 with significant anti-tumor efficacy and a favorable safety profile.
• This study highlights the success of a medicinal chemistry and polypharmacology approach for developing targeted cancer therapies.
• Pz-1 represents a promising therapeutic candidate for cancers driven by RET alterations.