ANAPLASTIC LYMPHOMA KINASE: SIGNAL TRANSDUCTION AND THERAPEUTIC VOYAGE OF ALK INHIBITORS

The identification of anaplastic lymphoma kinase (ALK) rearrangements in 2-5% of non-small cell lung cancer (NSCLC) patients led to the rapid clinical development of tyrosine kinase inhibitors. Anaplastic lymphoma kinase (ALK), a tyrosine kinase has attracted significant amount of attention because of its oncogenic potential and essential role in the pathogenesis of a wide variety of human cancers such as anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), squamous cell cancer of head and neck (SCCHN), breast cancer, neuro-blastoma and myo-fibroblastic tumor etc. To date nine ALK inhibitors have entered the clinical investigational phase for treatment of cancer. This review presents the role of ALK in certain cancers and signal transduction pathways, recent advances in drug development of ALK inhibitors and their synthetic routes. The review also presents the hit-drug evolution strategies of four ALK inhibitors and describes the current status of the small molecule ALK inhibitors isolated from natural sources and synthesized using variety of scaffolds. It anticipates to provide direction for design and synthesis of new compounds with privileged scaffolds possessing potent ALK inhibitory activity.