Combating Drug-Resistant Mutants of Anaplastic Lymphoma Kinase with Potent and Selective Type-I^1/2 Inhibitors by Stabilizing Unique DFG-Shifted Loop Conformation.

ABSTRACT: Targeted inhibition of anaplastic lymphoma kinase (ALK) dramatically improved therapeutic outcomes in the treatment of ALK-positive cancers, but unfortunately patients invariably progressed due to acquired resistance mutations in ALK. Currently available drugs are all type-I inhibitors bound to the ATP-binding pocket and are most likely to be resistant in patients harboring genetic mutations surrounding the ATP pocket. To overcome drug resistance, we rationally designed a novel kind of "bridge" inhibitor, which specially bind into an extended hydrophobic back pocket adjacent to the ATP-binding site of ALK. The novel type-I^1/2 inhibitors display excellent antiproliferation activity against ALK-positive cancer cells and appear superior to two clinically used drugs, crizotinib and

SUBMITTER: Pan P 

PROVIDER: S-EPMC5704298 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature