Targeting protein kinases for the development of anti-inflammatory drugs
Targeting protein kinases for the development of anti-inflammatory drugs
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DOI：
10.1016/j.ceb.2009.01.015
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发表时间：
2009-04-01
影响因子：
7.5
通讯作者：
Cohen, Philip
中科院分区：
文献类型：
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作者：
Cohen, Philip
近年来，蛋白激酶已成为制药行业研究最多的一类药物靶点，到目前为止，大约有10种蛋白激酶抑制剂已被批准用于癌症治疗。然而，对于可能需要服用数十年的慢性病治疗，是否也能开发出调节蛋白激酶活性的安全药物，这一问题仍未解决。许多抑制p38α丝裂原活化蛋白激酶（MAPK）的化合物已进入治疗类风湿性关节炎和银屑病的临床试验，但副作用使其无法进入Ⅲ期临床试验。在此，我简要回顾了以p38 MAPK为靶点的潜在问题，并讨论了其他调节先天免疫系统的蛋白激酶，如Tpl2、MAPKAP - K2/3、MSK1/2和IRAK4，它们可能是治疗慢性炎症性疾病更好的靶点，以及NIK，它是治疗多发性骨髓瘤（一种晚期B细胞恶性肿瘤）的一个有吸引力的靶点。
In recent years, protein kinases have become the pharmaceutical industry's most studied class of drug target, and some 10 protein kinase inhibitors have so far been approved for the treatment of cancer. However, whether safe drugs that modulate protein kinase activities can also be developed for the treatment of chronic diseases, where they may need to be taken for decades, is an issue that is still unresolved. A number of compounds that inhibit the p38 alpha MAPK have entered clinical trials for the treatment of rheumatoid arthritis and psoriasis, but side effects have prevented their progression to Phase III clinical trials. Here I briefly review the potential problems in targeting p38 MAPK and discuss other protein kinases that regulate the innate immune system, such as Tp12, MAPKAP-K2/3, MSK1/2 and IRAK4, which may be better targets for the treatment of chronic inflammatory diseases, and NIK, which is an attractive target for the treatment of multiple myeloma, a late stage B-cell malignancy.