Hinge binder modification into imidazopyridine for targeting actionable mutations of RET kinase

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• The RET proto-oncogene is a significant driver in multiple cancer types.
• Existing RET inhibitors face challenges with response rates and acquired resistance from mutations.
• There is a critical need for novel therapeutic strategies targeting RET alterations.

Purpose of the Study:

• To discover and characterize novel RET inhibitors.
• To evaluate the efficacy of new compounds against clinically relevant RET mutations and fusions.
• To investigate the binding mode and potential cardiotoxicity of the novel inhibitors.

Main Methods:

• Synthesis and screening of substituted imidazo[1,2-a]pyridine derivatives.
• In vitro enzymatic assays to determine IC50 values against RET variants.
• Induced-fit docking simulations to predict binding interactions.
• Cardiotoxicity assessment of the lead compounds.

Main Results:

• Identified novel imidazo[1,2-a]pyridine derivatives with potent RET inhibitory activity.
• Achieved low nanomolar IC50 values (as low as 11 nM) against three distinct RET point mutations.
• Demonstrated significant inhibition against three important RET fusions.
• Elucidated the binding mode through computational simulations and evaluated cardiotoxicity.

Conclusions:

• Substituted imidazo[1,2-a]pyridine derivatives represent a promising new class of RET inhibitors.
• These compounds show potential to overcome resistance mechanisms associated with RET mutations and fusions.
• Further investigation into their therapeutic potential and safety profile is warranted.