A protein kinase inhibitor (PKI) is a type of enzyme inhibitor that blocks the action of one or more protein kinases. Protein kinases are enzymes that phosphorylate (add a phosphate, or PO4, group) to a protein and can modulate its function.
The phosphate groups are usually added to serine, threonine, or tyrosine amino acids on the protein. Most kinases act on both serine and threonine, the tyrosine kinases act on tyrosine, and a number (dual-specificity kinases) act on all three. There are also protein kinases that phosphorylate other amino acids, including histidine kinases that phosphorylate histidine residues.
Phosphorylation regulates many biological processes, and protein kinase inhibitors can be used to treat diseases due to hyperactive protein kinases (including mutant or overexpressed kinases in cancer) or to modulate cell functions to overcome other disease drivers.
Clinical use Kinase inhibitors such as dasatinib are often used in the treatment of cancer and inflammation.
Some of the kinase inhibitors used in treating cancer are inhibitors of tyrosine kinases. The effectiveness of kinase inhibitors on various cancers can vary from patient to patient.
Examples There are several drugs launched or in development that target protein kinases and the receptors that activate them:
Name Target Company Class FDA approval Adavosertib WEE1 AstraZeneca Small molecule Afatinib EGFR/ErbB2 Boehringer Ingelheim Small molecule 2013 Non-small cell lung cancer Axitinib VEGFR1/VEGFR2/VEGFR3/PDGFRB/c-KIT Pfizer Small molecule 2012 Renal cell carcinoma Bosutinib Bcr-Abl / SRC Pfizer Small molecule 2012 Chronic myelogenous leukemia Cetuximab EGFR Imclone / BMS Monoclonal antibody 2006 Mar (SCCHN) Cobimetinib MEK Exelixis / Genentech-Roche Small molecule 2015 Nov (Advanced melanoma with BRAF mutation) in Combination with Vemurafenib (BRAF) Crizotinib ALK/Met Pfizer Small molecule 2011 Aug (NSCLC with Alk mutation) Cabozantinib RET/MET/VEGFR2 Exelixis Small molecule 2012 Nov (Metastatic medullary thyroid cancer) Dacomitinib EGFR/ErbB2/ErbB4 Pfizer Small molecule 2018 Non-small cell lung cancer Dasatinib multiple targets BMS Small molecule 2006 Entrectinib TrkA/TrkB/TrkC/ROS1/ALK Ignyta Small molecule 2004 Erdafitinib FGFR Janssen Small molecule 2019 Erlotinib EGFR Genentech Small molecule 2004 Fostamatinib Syk Rigel Pharmaceuticals / AstraZeneca Small molecule Gefitinib EGFR AstraZeneca Small molecule 2003 non-small cell lung cancer (NSCLC) Ibrutinib BTK Pharmacyclics Small molecule 2013 Imatinib Bcr-Abl Novartis Small molecule 2001 (CML), 2002 (GIST) Lapatinib EGFR/ErbB2 GSK Small molecule 2007 (HER2+ Breast) Lenvatinib VEGFR2 Eisai Co. Small molecule 2015 (thyroid), 2016 (renal) Mubritinib ? Takeda Small molecule Nilotinib Bcr-Abl Novartis Small molecule 2007 Pazopanib VEGFR2/PDGFR/c-kit GlaxoSmithKline Small molecule 2009 (RCC) Pegaptanib VEGF OSI/ Pfizer RNA Aptamer 2004 (AMD) Ruxolitinib JAK Incyte Small molecule 2011 (Myelofibrosis) Sorafenib multiple targets Onyx / Bayer Small molecule 2005 Dec (kidney) Sunitinib multiple targets SUGEN / Pfizer Small molecule 2006 Jan (RCC & GIST) SU6656 Src, others SUGEN Small molecule Tucatinib HER2 Seattle Genetics Small molecule 2020 Vandetanib RET/VEGFR/EGFR AstraZeneca Small molecule 2011 Vemurafenib BRAF Roche Small molecule 2011 Aug (Advanced melanoma with BRAF mutation)
Comparison of available agents