Discovery of A-910, a Highly Potent and Orally Bioavailable Dual MerTK/Axl-Selective Tyrosine Kinase Inhibitor

Area of Science:

• Oncology
• Immunology
• Medicinal Chemistry

Background:

• TAM receptor tyrosine kinases (MerTK and Axl) are crucial in cancer cell survival and immune evasion within the tumor microenvironment.
• Selective inhibition of MerTK and Axl may hinder cancer progression, reverse protumor myeloid cell phenotypes, and enhance antitumor immunity.

Purpose of the Study:

• To discover and characterize A-910, a novel, potent, and selective dual inhibitor of MerTK and Axl.
• To evaluate A-910's potential as an orally bioavailable tool compound for cancer immunotherapy research.

Main Methods:

• Structure-based medicinal chemistry campaign to identify A-910.
• Assessment of compound potency, selectivity, oral bioavailability, and in vivo target engagement.

Main Results:

• Discovery of A-910, a highly potent and selective dual MerTK/Axl inhibitor.
• A-910 demonstrated favorable oral bioavailability and exceptional kinome selectivity.
• Significant in vivo target engagement was observed with A-910.

Conclusions:

• A-910 represents a promising new chemical entity for targeting TAM kinases in cancer.
• The compound's properties support its use as an in vivo tool to explore dual MerTK/Axl inhibition for cancer immunotherapy.