First macrocyclic 3rd-generation ALK inhibitor for treatment of ALK/ROS1 cancer: Clinical and designing strategy update of lorlatinib

Eur J Med Chem. 2017 Jul 7:134:348-356. doi: 10.1016/j.ejmech.2017.04.032. Epub 2017 Apr 13.

Abstract

Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to 2nd-generation ALK inhibitors. Lorlatinib (PF-06463922) (6) is a 3rd-generation macrocyclic ALK-TKI that demonstrates many advantages over 2nd-generation ALK inhibitors. Lorlatinib has demonstrated decent kinase selectivity, promising pharmacokinetic profile, selective brain-penetration and strong antiproliferative activity in several ALK/ROS1-driven tumor models. The current review describes the activity spectrum, key events from discovery to clinical applications and the evidences that lorlatinib acts as an ALK/ROS1 inhibitor in clinical settings.

Keywords: Loratinib in phase II clinical trial; Lorlatinib third generation ALK/ROS1 inhibitor; Macrocyclic ALK inhibitor.

Publication types

  • Review

MeSH terms

  • Aminopyridines
  • Anaplastic Lymphoma Kinase
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Clinical Trials, Phase I as Topic
  • Clinical Trials, Phase II as Topic
  • Drug Evaluation, Preclinical
  • Humans
  • Lactams
  • Lactams, Macrocyclic / chemistry
  • Lactams, Macrocyclic / pharmacology
  • Lactams, Macrocyclic / therapeutic use*
  • Lung / drug effects*
  • Lung / metabolism
  • Lung / pathology
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Pyrazoles
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism

Substances

  • Aminopyridines
  • Antineoplastic Agents
  • Lactams
  • Lactams, Macrocyclic
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pyrazoles
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Protein-Tyrosine Kinases
  • ROS1 protein, human
  • Receptor Protein-Tyrosine Kinases
  • lorlatinib