Discovery of Novel Macrocyclic MERTK/AXL Dual Inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Members of the TAM receptor tyrosine kinase family, MERTK and AXL, are frequently overexpressed in various human cancers.
• These kinases are recognized as potential therapeutic targets due to their roles in tumor progression and immune evasion.

Purpose of the Study:

• To discover a novel class of macrocyclic dual MERTK/AXL inhibitors using structure-based drug design.
• To evaluate the potential of these inhibitors as therapeutic agents for cancer treatment, particularly nonsmall cell lung cancer.

Main Methods:

• Structure-based drug design approach informed by MERTK inhibitor knowledge.
• Synthesis and characterization of novel macrocyclic compounds.
• Biochemical assays (NanoBRET, phosphorylation assays) to assess target engagement and selectivity.
• Pharmacokinetic profiling and in vitro antitumor activity assessment against lung cancer cell lines.

Main Results:

• A novel class of macrocyclic dual MERTK/AXL inhibitors was discovered.
• The lead compound, designated 43, exhibited low-nanomolar inhibitory activity against both MERTK and AXL.
• Compound 43 demonstrated good selectivity over TYRO3 and FLT3, with confirmed target engagement and phosphorylation inhibition.
• Excellent pharmacokinetic properties, including high area under the curve (AUC) and long half-life, were observed for compound 43.
• Compound 43 displayed significant antitumor activity against nonsmall cell lung cancer cell lines.

Conclusions:

• Dual inhibition of MERTK and AXL represents a viable therapeutic strategy for certain cancers.
• The novel macrocyclic compound 43 is a potent and selective dual MERTK/AXL inhibitor with favorable drug-like properties.
• Compound 43 holds potential as a therapeutic agent for nonsmall cell lung cancer and possibly other malignancies driven by MERTK/AXL signaling.