Figures & data
Figure 1 The EML4–ALK rearrangement and downstream signaling.
Notes: ALK is a tyrosine kinase-containing receptor. EML4 and ALK are both found on the short arm of chromosome 2. The N-terminal portion of EML4 inverts and fuses to the intracellular region of ALK, forming the most common ALK rearrangement. The breakpoint within ALK is relatively conserved, occurring close to the 5′ end of exon 20. The fusion breakpoints within EML4 are more variable. Other upstream partners of ALK are not shown in this diagram. Typically, the extracellular domain and transmembrane helix are excluded from the resultant chimeric oncoprotein, incorporating only the cytoplasmic portion of ALK containing the tyrosine kinase domain. As ALK belongs to the insulin receptor superfamily, its tyrosine kinase domain shows homology to IGF-1R, and these receptors share overlapping growth pathway dependencies. ALK can signal by the RAS–MAPK, PI3K–mTOR, PLCγ, RAP1, JAK-STAT, and JUN pathways, leading to increased cell proliferation and survival.
Abbreviation: ALK, anaplastic lymphoma kinase.
Abbreviation: ALK, anaplastic lymphoma kinase.
Figure 2 Brigatinib structure.
Notes: Brigatinib is constructed around a bisanilinopyrimidine scaffold. This scaffold occupies the ATP-binding site of ALK in a U-shaped conformation. Two aniline groups attached on the C2 and C4 positions of the pyrimidine core are shown in red. The methoxy and extended solubilization groups bind to a pocket located under the hinge residue L1198 of ALK and part of the ribose binding pocket, respectively. A chlorine atom at C5 interacts with the gatekeeper residue L1196. The inclusion of the phosphorous-containing DMPO group was incorporated as a hydrogen bond acceptor on the C4 aniline, as shown in blue, and was found to increase activity against ALK by ~7-fold relative to the unsubstituted analog.
Abbreviations: ALK, anaplastic lymphoma kinase; ATP, adenosine triphosphate; DMPO, dimethylphosphine oxide.
Abbreviations: ALK, anaplastic lymphoma kinase; ATP, adenosine triphosphate; DMPO, dimethylphosphine oxide.
Table 1 Clinical outcomes of brigatinib, alectinib, and ceritinib after crizotinib treatment in patients with ALK-rearranged lung cancers
Table 2 Brigatinib activity against various ALK mutations
Table 3 AEs observed with brigatinib, alectinib, and ceritinib