<br/>Chromosomal rearrangements that lead to constitutively active anaplastic lymphoma kinase or ALK fusion proteins are observed in many cancers, particularly non-small cell lung cancer (NSCLC). While most cases of ALK positive NSCLC are initially highly responsive to ALK inhibitors, resistance invariably occurs within a year of treatment. This is a common trend in oncology as rapid evolution of drug resistance in cancers has historically necessitated the development of “next generation” kinase inhibitors. While new ALK inhibitors capable of overcoming crizotinib resistance have been recently developed, resistance quickly arose. These FDA approved pharmaceuticals include brigatinib, alectinib, ceritinib, and lorlatinib. Here we present in silico docking experiments performed with these ALK inhibitors and homology models of clinically relevant ALK variants in order to identify the unique protein-ligand features and interactions that result in drug resistance. These results will lead to a better understanding of how drug resistance arises in ALK and will aid in the development of next generation therapeutics.

Modeling the structural basis of resistance in ALK

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.