Discovery of N-[4-(Quinolin-4-yloxy)phenyl]benzenesulfonamides as Novel AXL Kinase Inhibitors

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• AXL kinase overexpression is implicated in various cancers, promoting proliferation, survival, and migration.
• AXL kinase is a promising therapeutic target for cancer treatment due to its critical roles in tumor progression.
• Resistance to existing therapies is a significant challenge in oncology, highlighting the need for novel therapeutic strategies.

Purpose of the Study:

• To identify and develop novel small molecule inhibitors targeting AXL kinase.
• To optimize lead compounds for potent AXL kinase inhibition and favorable pharmacokinetic properties.
• To evaluate the in vivo antitumor efficacy and safety of novel AXL kinase inhibitors.

Main Methods:

• Structure-Activity Relationship (SAR) studies were conducted for compound optimization.
• In vitro assays were used to determine AXL kinase inhibitory potency (low nanomolar range).
• In vivo xenograft models were utilized to assess antitumor activity, toxicity, and metastasis inhibition.

Main Results:

• A novel series of AXL kinase inhibitors were developed with low nanomolar potency.
• The lead compound exhibited a favorable pharmacokinetic profile.
• In xenograft models, lead compounds reduced tumor size by 40% and lung metastasis by 66% without observed toxicity.

Conclusions:

• Novel potent AXL kinase inhibitors with favorable drug-like properties were identified.
• The developed compounds show significant potential as anti-cancer therapeutics targeting AXL kinase.
• AXL kinase inhibition represents a viable strategy for reducing tumor growth and metastasis in cancer treatment.