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 and our subsequent linker design, and its docking analysis yielded novel -1,2,2-trisubstituted cyclopropane . 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--1,2,2-trisubstituted cyclopropane . 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.