Lorlatinib

A novel CNS-penetrant, ATP-competitive inhibitor of ALK/ROS1 with IC50 of 0.07/0.025 nM respectively; also inhibits ALK L1196M (IC50=0.7 nM) and exhibits selectivity >100-fold for ROS1 over 204 kinases; inhibits crizotinib-resistant mutant ROS1G2032R and ROS1L2026M and orally available in vivo.Lung Cancer Phase 3 Clinical (In Vitro) :Lorlatinib (PF-06463922) demonstrates significant cell activity against ALK and a large set of ALK clinical mutations with IC50 ranging from 0.2 nM-77 nM. Lorlatinib significantly inhibits cell proliferation and induces cell apoptosis in the HCC78 human NSCLC cells harboring SLC34A2-ROS1 fusions and the BaF3-CD74-ROS1 cells expressing human CD74-ROS1. Lorlatinib also shows potent growth inhibitory activity and induces apoptosis in the NSCLC cells harboring either non-mutant ALK or mutant ALK fusions. (In Vivo) :In rats, Lorlatinib (PF-06463922) displays low plasma clearance, a moderate volume of distribution, a reasonable half-life, low propensity for p-glycoprotein 1-mediated efflux and a bioavailability of 100%. In vivo, Lorlatinib shows cytoreductive antitumor efficacy in the NIH3T3 xenograft models expressing human CD74-ROS1 and Fig-ROS1 via inhibition in ROS1 phosphorylation and the downstream signaling molecules, as well as inhibition of the cell cycle protein Cyclin D1 in tumors. Lorlatinib also demonstrates marked antitumor activity in mice bearing tumor xenografts expressing EML4-ALK, EML4-ALK-L1196M, EML4-ALK-G1269A, EML4-ALK-G1202R or NPM-ALK.