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Mini reviews in medicinal chemistry 2020-May

Irreversible kinase inhibitors targeting to cysteine residues and their applications in cancer therapy.

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Debasis Das
Jian Hong

Mots clés

Abstrait

Protein kinases are the conserved enzymes that catalyze the phosphorilation process in cells and recognized as the targets for many diseases. FDA has approved many kinase inhibitors for the treatment of cancer and confirmed kinases as the relevant targets for drug discovery. Major approved drugs are ATP competitive reversible non-covalent inhibitors that achieve selectivity by recognition of specific binding pocket of the targeted kinases. In recent years scientists have paid more attention in the development of irreversible covalent kinase inhibitors to achieve better selectivity, less toxicity and side effects. Since 2013 six irreversible kinase inhibitors, including afatinib, ibrutinib, neratinib, dacomitinib and osimertinib, acalabrutinib have been approved by FDA for treatment of severe diseases like metastatic non-small cell lung cancer (NSCLC), mantel cell lymphoma (MCL) and HER2-positive breast cancer. These inhibitors are targeting cysteine residue of the kinases. Many irreversible kinase inhibitors that target to cysteine residue are in clinical trials for different cancers and yet to be approved to the market. We review this rapid progression and efforts of cysteine targeted irreversible kinase inhibitors research and developments towards future anticancer drugs.

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