Molecular Modeling of ALK L1198F and/or G1202R Mutations to Determine Differential Crizotinib Sensitivity.

ABSTRACT: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that has been recognized as a therapeutic target for EML4-ALK fusion-positive nonsmall cell lung cancer (NSCLC) treatment using type I kinase inhibitors such as crizotinib to take over the ATP binding site. According to Shaw's measurements, ALK carrying G1202R mutation shows reduced response to crizotinib (IC₅₀ = 382 nM vs. IC₅₀ = 20 nM for wild-type), whereas L1198F mutant is more responsive (IC₅₀ = 0.4 nM). Interestingly, the double mutant L1198F/G1202R maintains a similar response (IC₅₀ = 31 nM) to the wild-type. Herein we conducted molecular modeling simulations to elucidate the varied crizotinib sensitivities in three mutants carrying L1198F and/or G1202R. Both L1198 and G1202 ar

SUBMITTER: Chuang YC 

PROVIDER: S-EPMC6684801 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature