Table 2.

Characteristics and structures of first-, second-, and third-generation of anaplastic lymphoma kinase inhibitors.

First-Generation Inhibitor
Crizotinib Off-targets: ROS1, c-MET No CNS penetration Sensitive: R1275Q Resistant: F1174L/V
Second-Generation Inhibitors
TAE-684 Sensitive: R1275Q, F1174L Discontinued		Ceritinib Off-targets: IGFR1, ROS1 CNS penetration Resistant: F1174L/C
ASP3026 Off-targets: ROS1, ACK Resistant: L1196M		Brigatinib Off-targets: ROS1, EGFR CNS penetration Sensitive: all NBL-associated point mutations
Ensartinib Sensitive: R1275Q, F1174L		AZD3463 Off-target: IGFR1 Sensitive: NBL hotspot mutations
CEP-37440 Off-target: FAK CNS penetration Sensitive: NBL hotspot mutations		Alectinib Sensitive: all NBL-associated point mutations, plus amplifications
Belizatinib Off-targets: IGFR1, JAK2, TrkA/B/C, c-Src CNS penetration Sensitive: R1275Q, L1196M		Entrectinib Off-targets: ROS1, TrkA/B/C CNS penetration Sensitive: ALK amplifications
Third-Generation Inhibitors
Lorlatinib Off-target: ROS1 CNS penetration Sensitive: NBL hotspot mutations		Repotrectinib Off-targets: ROS1, TrkA/B/C CNS penetration Sensitive: all NBL-associated point mutations

Abbreviations: ROS1: ROS pro-oncogene 1; c-MET: hepatocyte growth factor; CNS: central nervous system; IGFR1: insulin-like growth factor; ACK: activated CDC24 kinase; EGFR: epidermal growth factor receptor; NBL: neuroblastoma; FAK: focal adhesive kinase; JAK2: Janus kinase 2; Trk: tropomyosin receptor kinase.