PF-2341066

PF-2341066

PF-2341066, also known as crizotinib, is a small molecule inhibitor of the receptor tyrosine kinases ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1). It is primarily used in the treatment of non-small cell lung cancer (NSCLC) that is ALK-positive or ROS1-positive. Crizotinib was developed by Pfizer and received approval from the U.S. Food and Drug Administration (FDA) in 2011.

Mechanism of Action

Crizotinib functions by inhibiting the activity of ALK and ROS1, which are involved in the growth and proliferation of cancer cells. ALK and ROS1 are part of a family of proteins known as receptor tyrosine kinases, which play a critical role in the signaling pathways that regulate cell division and survival. In certain cancers, these kinases are abnormally activated due to genetic mutations or rearrangements, leading to uncontrolled cell growth. By blocking these kinases, crizotinib can effectively halt the progression of tumors that depend on these pathways.

Clinical Use

Crizotinib is indicated for the treatment of patients with metastatic NSCLC whose tumors are ALK-positive or ROS1-positive. The presence of these genetic alterations is typically determined using a diagnostic test, such as fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS).

Dosage and Administration

Crizotinib is administered orally, with the recommended dose being 250 mg twice daily. Treatment continues until disease progression or unacceptable toxicity occurs. Dose adjustments may be necessary based on individual patient tolerance and side effects.

Side Effects

Common side effects of crizotinib include vision disorders, nausea, diarrhea, vomiting, edema, and constipation. More serious adverse effects can include hepatotoxicity, interstitial lung disease, and QT interval prolongation. Regular monitoring of liver function and cardiac health is recommended during treatment.

Resistance

Resistance to crizotinib can develop over time, often due to secondary mutations in the ALK or ROS1 genes that prevent the drug from binding effectively. Research is ongoing to develop next-generation ALK inhibitors that can overcome these resistance mechanisms.

Research and Development

Crizotinib was discovered through a high-throughput screening process aimed at identifying inhibitors of the MET receptor tyrosine kinase. Subsequent studies revealed its potent activity against ALK and ROS1, leading to its development as a targeted therapy for NSCLC.

Also see

• Non-small cell lung cancer
• Receptor tyrosine kinase
• ALK inhibitors
• ROS1-positive cancer