Brigatinib, Free Base

Soluble in DMSO. Brigatinib, also known as AP26113, inhibited ALK, IGF-1R, and InsR kinases with IC50 values of 0.37 nM, 24.9 nM, and 196 nM, respectively. It blocked the viability of Karpas 299 cells (ALK+) with an IC50 of 29 nM in vitro. It demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas) and H3122 (non-small-cell lung cancer [NSCLC]) xenografts. Huang W.S., et al. 'Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.' J. Med. Chem. 59: 4948-4964 (2016). Brigatinib potently inhibited ALK and ROS1 kinases, with a high selectivity over >250 other kinases. Among a panel of ALK+ cell lines, brigatinib inhibited native ALK (IC50, 10 nmol/L) with 12-fold higher potency than crizotinib. Excellent efficacy of brigatinib was also observed in mice with ALK+ tumors. Zhang S., et al. 'The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models.' Clin. Cancer Res. 22: 5527-5538 (2016). For patients with ALK-positive NSCLC who had not previously received an ALK inhibitor, progression-free survival was significantly longer among patients treated with brigatinib than among those treated with crizotinib. Camidge D.R., et al. 'Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer.' N. Engl. J. Med. 379: 2027-2039 (2018).