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

Abstract

In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.

Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase–Positive Non–Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial

“…20 In preclinical models, brigatinib potently inhibited all ALK resistance mutations tested, including G1202R, and overcame mechanisms of resistance to other ALK inhibitors at clinically achievable brigatinib levels. 21 In an ongoing phase I/II clinical trial (NCT01449461), brigatinib yielded promising antitumor activity (confirmed ORR, 62%; median PFS, 12.9 months) in patients with advanced ALK-positive NSCLC previously treated with crizotinib.…”

The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models

“…In particular, major unique mutational liabilities of ceritinib (L1152R/P and L1198F) and alectinib (I1171N and V1180L), are shown to result from their differing molecular structures and interactions with ALK compared with brigatinib. Notably, the dimethylphosphine oxide moiety present on the C4 aniline of brigatinib is critical for balancing ALK potency and selectivity over the highly homologous IGF-1R and INSR kinases (30).…”

Targeting ALK: Precision Medicine Takes on Drug Resistance

“…For example, brigatinib (AP26113) is a potent ALK inhibitor that inhibits most crizotinib-resistant ALK mutants (124–129). In the phase II ALTA trial, 222 patients with advanced ALK -positive NSCLC who progressed on crizotinib were randomized to two different dosing schedules of brigatinib.…”