Progression and expansion of ALK inhibitors against NSCLC: A dual target approach

Abstract

ALK gene is a member of the tyrosine kinase receptor family found on chromosome 2 (2p23) that plays an important role in the progression of the non-small cell lung cancer (NSCLC). Since the ALK inhibitors such as Crizotinib, Ceritinib, Brigatinib, Alectinib and Lorlatinib, was endorsed for the treatment of advanced NSCLC linked to ALK gene rearrangement. But eventually, patients become resistant to the medication, which will result in treatment failure. However, treatment for NSCLC could be greatly advanced by the development of dual inhibitors that target ALK in addition to other oncogenic pathways like ROS1, c-MET, EGFR, etc. These strategies seek to improve therapy efficacy, address resistance mechanisms, and provide treatment alternatives for patients with intricate molecular profiles. The aim of this review is to summarize the introduction to ALK and the synergy between ALK and other anti-tumor targets, recent developments in the synthesis of various dual inhibitors of the ALK. We also thoroughly discussed their design concepts, structure-activity relationships (SARs), preclinical and clinical data as well as in silico studies to provide ideas for further development of novel ALK based dual inhibitors.

Keywords: ALK; Dual inhibition; Gene rearrangement; NSCLC; Resistance; etc.