Discovery Chemistry Research, ArromaxPharmatech Co. Ltd. Sangtian Island Innovation Park, No. 1 Huayun Road, Suzhou 215123, China.
Mini Rev Med Chem. 2020;20(17):1732-1753. doi: 10.2174/1389557520666200513121524.
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.
蛋白激酶是细胞内磷酸化过程的保守酶，被认为是许多疾病的靶点。美国食品和药物管理局已经批准了许多激酶抑制剂用于癌症治疗，并证实激酶是药物发现的相关靶点。主要批准的药物是 ATP 竞争性可逆非共价抑制剂，通过识别靶向激酶的特定结合口袋来实现选择性。近年来，科学家们一直致力于开发不可逆的共价激酶抑制剂，以实现更好的选择性、更低的毒性和副作用。自 2013 年以来，已有七种不可逆激酶抑制剂（Irreversible Kinase Inhibitors，IKIs），包括阿法替尼、伊布替尼、奈拉替尼、达可替尼、奥希替尼、阿卡替尼和泽布替尼，被美国食品和药物管理局批准用于治疗转移性非小细胞肺癌（Metastatic Non-Small Cell Lung Cancer，NSCLC）、套细胞淋巴瘤（Mantle Cell Lymphoma，MCL）和 HER2 阳性乳腺癌等严重疾病。这些抑制剂针对激酶的半胱氨酸残基。许多针对半胱氨酸残基的 IKIs 正在临床试验中用于治疗不同的疾病，尚未获得批准。我们回顾了近年来在寻找新型半胱氨酸靶向 IKIs 作为药物方面所做的研究和努力。
