Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK)

Abstract

As a receptor tyrosine kinase of insulin receptor (IR) subfamily, anaplastic lymphoma kinase (ALK) has been validated to play important roles in various cancers, especially anaplastic large cell lymphoma (ALCL), nonsmall cell lung cancer (NSCLC), and neuroblastomas. Currently, five small-molecule inhibitors of ALK, including Crizotinib, Ceritinib, Alectinib, Brigatinib, and Lorlatinib, have been approved by the U.S. Food and Drug Administration (FDA) against ALK-positive NSCLCs. Novel type-I1/2 and type-II ALK inhibitors with improved kinase selectivity and enhanced capability to combat drug resistance have also been reported. Moreover, the “proteolysis targeting chimera” (PROTAC) technique has been successfully applied in developing ALK degraders, which opened a new avenue for targeted ALK therapies. This review provides an overview of the physiological and biological functions of ALK, the discovery and development of drugs targeting ALK by focusing on their chemotypes, activity, selectivity, and resistance as well as potential therapeutic strategies to overcome drug resistance.

Urolithin C increases glucose‐induced ERK activation which contributes to insulin secretion

“…Indeed, we found that inhibition of insulin signalling with GSK1838705A blocked the stimulating effect of 20 µM urolithin C on glucose-induced ERK1/2 as its phosphorylation level returned to 8.3 mM glucose control value. It is worth mentioning that GSK1838705A inhibits the closely related IR and IGF-1R as well as anaplastic lymphoma kinase (ALK) which is also a member of the IR subfamily [37,38,51]. Nonetheless, INS-1 cells express IR but are likely lacking IGF-1R [36].…”

Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies

“…Recently, a VHL-recruiting ALK PROTAC based on brigatinib, named SIAIS117, was found to be more potent than brigatinib in inhibiting the growth of G1202R mutant ALK-expressing 293T cells by inducing G1202R mutant ALK degradation [ 52 ]. The PROTACs against ALK have also been briefly discussed in a review by Kong et al [ 53 ].…”

Proteolysis targeting chimeras (PROTACs) in cancer therapy

“…Additional PROTACs targeting other components of the transcription machinery include those based on inhibitors of CDK9 or SMARCA2/4 [ 45 – 49 ]. PROTACs based on inhibitors targeting ALK or CDK6 kinases or based on inhibitors of the BCL6, BCL-XL or MCL1 apoptotic machinery components have also been developed [ 50 – 55 ]. Supplementary Table 2 shows a complete list of PROTACs explored in preclinical studies.…”