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

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