Insights into ALK acquired resistance were used to define drug design strategies that led to the discovery of lorlatinib (PF-06463922), a novel macrocyclic inhibitor of ALK/ROS1. Structure based drug design, lipophilic efficiency and physicochemical property-based optimization provided inhibitors with overlapping broad spectrum potency, low transporter efflux, and brain penetration. Lorlatinib is in Phase 3 clinical trials for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC) and was given Breakthrough Therapy status by the FDA in 2016.

Mechanisms of ALK acquired resistance and the discovery of lorlatinib (PF-06463922), a macrocyclic ALK/ROS1 inhibitor for the treatment of resistant and metastatic NSCLC

2019 Spring National Meeting

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