tcsc4278 Brigatinib

Brigatinib is a highly potent and selective ALK inhibitor, with IC₅₀ of 0.6 nM.

IC50 & Target: IC50: 0.6 nM (ALK)^[1]

In Vitro: Brigatinib potently inhibits the in vitro kinase activity of ALK (IC₅₀, 0.6 nM) and all five mutant variants tested, including G1202R (IC₅₀, 0.6-6.6 nM). Brigatinib demonstrates a high degree of selectivity, only inhibiting 11 additional native or mutant kinases with IC₅₀ <10 nM. These include ROS1, FLT3, and mutant variants of FLT3 (D835Y) and EGFR (L858R; IC₅₀, 1.5-2.1 nM). Brigatinib exhibits more modest activity against EGFR with a T790M resistance mutation (L858R/T790M), native EGFR, IGF1R, and INSR (IC₅₀, 29-160 nM) and does not inhibit MET (IC₅₀ >1000 nM). In cellular assays, brigatinib inhibits ALK and ROS1 with IC₅₀s of 14 and 18 nM, respectively. Brigatinib inhibits FLT3 and IGF-1R with about 11-fold lower potency (IC₅₀, 148-158 nM) and inhibits mutant variants of FLT3 and EGFR with 15- to 35-fold lower potency (IC₅₀, 211-489 nM). Brigatinib inhibits cell growth with GI₅₀ values ranging from 503 to 2,387 nM in three ALK-negative ALCL and NSCLC cell lines^[1]. Brigatinib inhibits ALK activity and abrogates proliferation of ALK addicted neuroblastoma cell lines, with IC₅₀ of 75.27 ± 8.89 nM. Brigatinib inhibits both the ALK-I1171N and the ALK-G1269A mutant receptors at 10 and 4 nM levels, respectively^[3].

In Vivo: Brigatinib (10, 25, or 50 mg/kg once daily, p.o.) leads to a dose-dependent inhibition of tumor growth in ALK⁺ Karpas-299 (ALCL) and H2228 (NSCLC) xenograft mouse models. Brigatinib markedly enhances survival of mice bearing ALK⁺ brain tumors compared with crizotinib^[1]. Brigatinib (10, 25, 50 mg/kg, p.o.) results in dose-dependent antitumor activity, with tumor regressions in a mouse model of NSCLC^[2].