Latest perspectives of orally bioavailable 2,4-diarylaminopyrimidine analogues (DAAPalogues) as anaplastic lymphoma kinase inhibitors: discovery and clinical developments

摘要: The course of anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) therapy has improved impressively. Food and Drug Administration (FDA) approved crizotinib (Xalkori, Pfizer) as a first-in-class tyrosine inhibitor (TKI) that demonstrated substantial objective response rate (ORR) remarkable progression-free survival (PFS). However, acquired resistance to is still major concern especially the central nervous system (CNS) remains most common sites relapse. To combat disease resistance, limited PFS poor CNS exposure exhibited by led discovery numerous next generation ALK-TKIs surprisingly them are 2,4-Diarylaminopyrimidine Analogues (DAAPalogues). date, DAAPalogues have been investigated extensively display their superior potency against targets ALK/ROS1. This review describes hit-to-drug evolution strategies, activity spectra, milestones related medicinal chemistry efforts scalable synthetic pathways clinically emerging DAAPalouges which either progressing investigational or preclinical candidates. In addition, significance treat patients with ALK+-NSCLC in clinical settings detailed. beneficial for chemists researchers contributing discovering overcome existing issues drug process.