crizotinib

crizotinib
Name	crizotinib
Tradename	Xalkori
ATC prefix	L01
ATC suffix	EX05
PubChem	11626560
CAS number	877399-52-5
Molecular weight	450.42

crizotinib is a tyrosine kinase inhibitor used in the treatment of non-small cell lung cancer (NSCLC) and anaplastic large cell lymphoma (ALCL), as approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA). It is marketed by Pfizer under the trade name Xalkori. The development of crizotinib involved collaborations between Pfizer, University of California, Los Angeles (UCLA), and the National Cancer Institute (NCI). Researchers from Stanford University and University of Texas Southwestern Medical Center also contributed to the understanding of its mechanism of action.

Introduction

Crizotinib has been shown to be effective in treating patients with ALK-positive NSCLC, a subtype of lung cancer characterized by the presence of the anaplastic lymphoma kinase (ALK) gene fusion. This discovery was facilitated by the work of scientists at Harvard University, Massachusetts Institute of Technology (MIT), and Dana-Farber Cancer Institute. The American Cancer Society and the National Institutes of Health (NIH) have supported research into the biology of ALK-positive tumors, which has informed the development of crizotinib. Additionally, studies published in the Journal of Clinical Oncology and New England Journal of Medicine have demonstrated the efficacy of crizotinib in clinical trials.

Medical_uses

Crizotinib is used to treat patients with metastatic NSCLC who have the ALK gene rearrangement or ROS1 gene rearrangement, as detected by an FDA-approved test, such as the Vysis ALK Break Apart FISH Probe Kit developed by Abbott Laboratories. The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) have issued guidelines for the use of crizotinib in the treatment of NSCLC. Researchers at University of Chicago and Johns Hopkins University have investigated the potential of crizotinib in combination with other therapies, such as chemotherapy and radiation therapy, to enhance treatment outcomes. The National Comprehensive Cancer Network (NCCN) has also developed guidelines for the use of crizotinib in the treatment of ALCL.

Side_effects

Common side effects of crizotinib include vision disorders, such as blurred vision and double vision, as well as gastrointestinal disorders, such as nausea and vomiting. Patients treated with crizotinib may also experience hepatotoxicity, which can be monitored using liver function tests developed by Roche Diagnostics and Siemens Healthineers. The FDA and EMA have issued warnings about the potential for crizotinib to cause pneumonitis, a type of lung inflammation, which can be diagnosed using computed tomography (CT) scans and positron emission tomography (PET) scans developed by General Electric and Philips Healthcare. Researchers at University of California, San Francisco (UCSF) and Memorial Sloan Kettering Cancer Center have investigated the mechanisms underlying these side effects.

Pharmacology

Crizotinib works by inhibiting the activity of the ALK and ROS1 tyrosine kinases, which are involved in the signaling pathways that promote cell growth and survival. The University of Pennsylvania and Columbia University have conducted research on the pharmacokinetics and pharmacodynamics of crizotinib, which has informed its dosing and administration. Crizotinib is metabolized by the cytochrome P450 enzyme system, specifically by the CYP3A4 and CYP3A5 isoforms, which are also involved in the metabolism of other tyrosine kinase inhibitors developed by Novartis and AstraZeneca. The European Organization for Research and Treatment of Cancer (EORTC) has developed guidelines for the use of crizotinib in combination with other therapies.

History

The development of crizotinib involved a collaboration between Pfizer and University of California, Los Angeles (UCLA), which began in the early 2000s. Researchers at UCLA and Stanford University identified the ALK gene fusion as a potential target for cancer therapy, and Pfizer developed crizotinib as a small molecule inhibitor of ALK. The National Cancer Institute (NCI) and the American Association for Cancer Research (AACR) have supported research into the biology of ALK-positive tumors, which has informed the development of crizotinib. Clinical trials of crizotinib were conducted at MD Anderson Cancer Center and University of Texas Southwestern Medical Center, among other institutions.

Synthesis

The synthesis of crizotinib involves a multi-step process that requires the use of specialized reagents and equipment, such as those developed by Sigma-Aldrich and Thermo Fisher Scientific. Researchers at Massachusetts Institute of Technology (MIT) and California Institute of Technology (Caltech) have developed new methods for the synthesis of crizotinib, which have improved its yield and purity. The American Chemical Society (ACS) and the Royal Society of Chemistry (RSC) have published articles on the synthesis and characterization of crizotinib, which have informed its development as a pharmaceutical agent. Additionally, companies such as BASF and Merck KGaA have developed processes for the large-scale synthesis of crizotinib.

Category:Antineoplastic drugs