Small Molecule Inhibitors of ALK

Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK)

“…Blockading of the aberrant ALK signaling pathways by small-molecule inhibitors has been validated as an effective way to inhibit the growth of ALK-positive cancer cells. Over the past decade, intensive efforts have thus been made to develop ALK inhibitors with different chemotypes. ,, At present, five ALK inhibitors, including 1 , 2 , 4 , 5 and 11 , have been approved by the FDA for the treatment of ALK-positive NSCLCs. ,,, …”

“…A series of clinical response data, including PROFILE 1001 (phase I, 2008), PROFILE 1005 (phase I/II, 2011), PROFILE 1007 (phase III, 2012), and PROFILE 1014 (phase III, 2014), confirmed that 1 is superior to the standard chemotherapy (pemetrexed or docetaxel) in the treatment of advanced or metastatic EML4-ALK NSCLCs, − which led to the approval of 1 for the treatment of ALK-positive NSCLC in 2011. In addition, compound 1 also shows excellent efficacy in ALK-positive IMTs and Kelly neuroblastomas induced by gene amplification and/or mutations. , Unfortunately, the success of 1 was overshadowed by the rapid emergence of drug resistance. , The most frequently acquired mutations are L1196M, C1156Y, G1202, and G1269A/S (Figure B). Moreover, the 1151Tins, L1152R, I1171T/N/S, F1174 V/L/C, G1202R, D1203N, S1206Y, and V1180L mutations were also reported to be able to confer resistance to 1 (Figure A).…”

“…Moreover, the 1151Tins, L1152R, I1171T/N/S, F1174 V/L/C, G1202R, D1203N, S1206Y, and V1180L mutations were also reported to be able to confer resistance to 1 (Figure A). The emergence of drug resistance and increasing need for better drugs led to the development and approval of the second- and third-generation ALK inhibitors (Figures , , , and ), including 3 , 4 , 5 , and 11 . ,,,, …”

“…Besides, the unique DMPO acts as a H-bond acceptor, effectively fostering the intramolecular interactions and stabilizing its U-shaped conformation. In both enzyme-based and cellular assays, compound 5 exhibited low nanomolar IC 50 against WT ALK/ROS1/EGFR and a broad panel of drug-resistant mutants of ALK ,,,, (shown in Table ). In addition, compound 5 demonstrated remarkable efficacy in multiple mouse models of NSCLCs without significant side effects .…”

“…In spite of the great efforts that have been made in the past decade, drug resistance still remains a crucial problem. As shown in Figure , acquired secondary mutations, and gene amplification and/or increased copy number account for about one-third of drug resistance cases. ,, In addition, the activation of alternative signaling pathways and epithelial–mesenchymal transition (EMT) can also compromise therapeutic efficacy . To overcome drug resistance and improve kinase selectivity, novel type-I 1 / 2 and type-II inhibitors of ALK that can probe the extended hydrophobic pocket were developed. − Particularly, inspired by the success of the “proteolysis targeting chimera” (PROTAC) technique in drug discovery, several ALK PROTACs have already been developed. − This review provides a general outline of the structure, biological functions, and aberrations of ALK, the discovery and development of ALK drugs, structural rationales for drug resistance, and potential anti-resistance therapeutic strategies.…”