Irreversible Kinase Inhibitors Targeting Cysteine Residues and their Applications in Cancer Therapy.

Abstract

Protein kinases are conserved enzymes that catalyse the phosphorylation process in cells. They are recognized as the targets for many diseases. The FDA has approved many kinase inhibitors for the treatment of cancer and confirmed kinases as relevant targets for drug discovery. Major approved drugs are ATP competitive reversible non-covalent inhibitors that achieve selectivity by recognition of specific binding pockets of targeted kinases. In recent years, scientists have paid attention on developing irreversible covalent kinase inhibitors to achieve better selectivity, less toxicity and side effects. Since 2013, seven Irreversible Kinase Inhibitors (IKIs), including; afatinib, ibrutinib, neratinib, dacomitinib, osimertinib, acalabrutinib and zanubrutinib have been approved by the FDA for treatment of severe diseases, like; Metastatic Non-Small Cell Lung Cancer (NSCLC), Mantle Cell Lymphoma (MCL) and HER2-positive breast cancer. These inhibitors target the cysteine residues of kinases. Many IKIs that target cysteine residues are in clinical trials for different diseases and are yet to be approved. We have reviewed the research done and efforts made for finding novel cysteine targeted IKIs as drugs in the recent years.