Pyrazolylamine Derivatives Reveal the Conformational Switching between Type I and Type II Binding Modes of Anaplastic Lymphoma Kinase (ALK)

Most
anaplastic lymphoma kinase (ALK) inhibitors adopt a type I
binding mode, but only limited type II ALK structural studies are
available. Herein, we present the structure of ALK in complex with N1-(3-4-[([5-(tert-butyl)-3-isoxazolyl]­aminocarbonyl)­amino]-3-methylphenyl-1H-5-pyrazolyl)-4-[(4-methylpiperazino)­methyl]­benzamide
(5a), a novel ALK inhibitor adopting a type II binding
mode. It revealed binding of 5a resulted in the conformational
change and reposition of the activation loop, αC-helix, and
juxtamembrane domain, which are all important domains for the autoinhibition
mechanism and downstream signal pathway regulation of ALK. A structure–activity
relationship study revealed that modifications to the structure of 5a led to significant differences in the ALK potency and altered
the protein structure of ALK. To the best of our knowledge, this is
the first structural biology study to directly observe how changes
in the structure of a small molecule can regulate the switch between
the type I and type II binding modes and induce dramatic conformational
changes.