Structure-Based Drug Discovery of Triazine Derivatives as Potent and Orally Bioavailable AXL Inhibitors for Cancer...

Area of Science:

• Oncology
• Pharmacology
• Drug Discovery

Background:

• Receptor tyrosine kinase AXL is frequently overexpressed in diverse cancers.
• AXL overexpression contributes to tumor resistance against immunotherapy and chemotherapy.

Purpose of the Study:

• To discover and characterize a novel AXL inhibitor for cancer therapy.
• To evaluate the therapeutic potential of the AXL inhibitor, 4j, alone and in combination with anti-PD-1 therapy.

Main Methods:

• Structure-based drug design and SAR-driven optimization were employed to identify compound 4j.
• In vitro assays assessed enzymatic activity, antiproliferative effects, and selectivity.
• Pharmacokinetic profiling and in vivo studies evaluated bioavailability, drug properties, and therapeutic efficacy.

Main Results:

• Compound 4j demonstrated potent enzymatic inhibition and antiproliferative activity with high selectivity.
• 4j exhibited favorable oral bioavailability and acceptable pharmacokinetic parameters.
• Combination therapy with 4j and an anti-PD-1 antibody showed significant synergistic effects and promising in vivo therapeutic efficacy.

Conclusions:

• The novel AXL inhibitor 4j possesses excellent drug-like properties and potent anti-cancer activity.
• AXL inhibition combined with anti-PD-1 therapy presents a promising strategy for treating malignant tumors.
• Compound 4j is a potential innovative therapeutic candidate for oncological indications.