Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic...

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• Anaplastic lymphoma kinase (ALK) mutations drive non-small-cell lung cancer (NSCLC) growth.
• Secondary ALK mutations confer resistance to existing ALK inhibitors.
• Novel therapeutic strategies are needed to overcome ALK inhibitor resistance.

Purpose of the Study:

• To design and synthesize novel ALK inhibitors targeting resistance mutations.
• To identify a potent and selective clinical candidate for ALK-positive NSCLC.
• To evaluate the efficacy of brigatinib in preclinical models.

Main Methods:

• Structure-based drug design of 2,4-diarylaminopyrimidine derivatives.
• Synthesis and chemical characterization of novel compounds.
• Biochemical and cell-based assays to assess ALK inhibition and cellular activity.
• In vivo efficacy studies in ALK-positive xenograft models.

Main Results:

• Identification of brigatinib, a potent and selective ALK inhibitor.
• Brigatinib demonstrates low nanomolar IC50s against wild-type ALK and resistant mutants.
• Favorable ADME properties attributed to the phosphine oxide moiety.
• Significant efficacy in preclinical models of ALK-positive NSCLC and ALCL.

Conclusions:

• Brigatinib is a promising clinical candidate for treating ALK-positive NSCLC, including resistant forms.
• The phosphine oxide group is a key structural feature for potency and selectivity.
• Brigatinib warrants further clinical investigation for ALK-driven malignancies.