Discovery and Characterization of Potent, Selective, and Orally Bioavailable 7-Azaindazole AXL Receptor Tyrosine...

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• High expression of receptor tyrosine kinase AXL correlates with poor prognosis and treatment resistance in various cancers.
• Targeting AXL is a potential strategy to overcome resistance to standard cancer therapies.
• The therapeutic window and efficacy of existing AXL inhibitors in blocking tumor signaling remain unclear.

Purpose of the Study:

• To design and optimize novel 7-azainazole-based AXL inhibitors.
• To identify a tool compound for in vivo validation of AXL inhibition.
• To discover a clinical development candidate with improved properties for treating AXL-driven cancers.

Main Methods:

• Structure-activity relationship (SAR) studies guided the optimization of 7-azainazole derivatives.
• In vivo studies were conducted using a tool compound to assess anti-tumor efficacy.
• Lead optimization focused on achieving desired potency, selectivity, bioavailability, and safety profiles.

Main Results:

• A novel series of 7-azainazole AXL inhibitors was successfully developed.
• An optimized tool compound demonstrated significant tumor volume reduction in combination therapy.
• Lead compound 68 exhibited favorable potency, kinome selectivity, oral bioavailability, and safety.
• Clinical development candidate AB801 was identified through further optimization.

Conclusions:

• The SAR-driven optimization yielded potent and selective AXL inhibitors.
• The developed compounds, including AB801, represent promising therapeutic agents for AXL-related cancers.
• This research provides a foundation for advancing AXL-targeted therapies in clinical settings.