Discovery of AB801, a Potent and Selective Inhibitor of AXL Receptor Tyrosine Kinase for Use in Cancer Therapy

Area of Science:

• Oncology
• Drug Discovery
• Molecular Biology

Background:

• AXL receptor tyrosine kinase (AXL) is highly expressed in many cancers.
• AXL signaling contributes to therapeutic resistance and poor patient outcomes.
• Targeting AXL offers a potential strategy to improve cancer treatment efficacy.

Purpose of the Study:

• To report the discovery and preclinical characterization of AB801, a novel AXL inhibitor.
• To detail the structure-based design, SAR optimization, and synthetic chemistry of AB801.
• To evaluate the potential of AB801 as a therapeutic agent in various cancers.

Main Methods:

• Structure-based drug design and structure-activity relationship (SAR) driven optimization.
• Preclinical pharmacokinetic (PK) studies and in vitro/in vivo assays.
• Clinical evaluation in healthy volunteers and patients with advanced solid tumors and NSCLC.

Main Results:

• Discovery of AB801, a potent, selective, and orally bioavailable AXL inhibitor.
• Comprehensive preclinical characterization of AB801's pharmacological properties.
• Successful dosing in healthy volunteers and initiation of clinical trials in cancer patients.

Conclusions:

• AB801 represents a promising novel therapeutic candidate targeting AXL.
• The drug's favorable properties support its ongoing clinical evaluation.
• AB801 has potential in treating advanced solid tumors and non-small cell lung cancer, alone or in combination therapy.