Discovery of Novel and Highly Selective Cyclopropane ALK Inhibitors through a Fragment-Assisted, Structure-Based Drug Design

Fragment
screening is frequently used for hit identification. However, there
was no report starting from a small fragment for the development of
an anaplastic lymphoma kinase (ALK) inhibitor, despite the number
of ALK inhibitors reported. We began our research with the fragment
hit F-1 and our subsequent linker design, and its docking
analysis yielded novel cis-1,2,2-trisubstituted cyclopropane 1. The fragment information was integrated with a structure-based
approach to improve upon the selectivity over tropomyosin receptor
kinase A, leading to the potent and highly selective ALK inhibitor,
4-trifluoromethylphenoxy-cis-1,2,2-trisubstituted
cyclopropane 12. This work shows that fragments become
a powerful tool for both lead generation and optimization, such as
the improvement of selectivity, by combining them with a structure-based
drug design approach, resulting in the fast and efficient development
of a novel, potent, and highly selective compound.