曲美替尼
达布拉芬尼
MEK抑制剂
威罗菲尼
塞鲁美替尼
神经母细胞瘤RAS病毒癌基因同源物
激酶
癌症
肿瘤科
克拉斯
作者
Nicolas Dumaz,Céleste Lebbé
出处
期刊:Current Opinion in Oncology
[Ovid Technologies (Wolters Kluwer)]
日期:2021-03-01
卷期号:33 (2): 120-126
被引量:4
标识
DOI:10.1097/cco.0000000000000708
摘要
Purpose of review Although immune checkpoint inhibitors and small molecule inhibitors targeting the MAPK pathway have revolutionized the management of metastatic melanoma, long-term disease control occurs only for a minority of patients because of multiple resistance mechanisms. One way to tackle resistance is to develop the next-generation of RAF, MEK and ERK inhibitors using our understanding of the molecular mechanisms that fine-tune the MAPK pathway. Recent findings Studies on the regulation of the MAPK pathway have revealed a dominant role for homo-dimerization and hetero-dimerization of RAF, MEK and ERK. Allosteric inhibitors that break these dimers are, therefore, undergoing various stages of preclinical and clinical evaluation. Novel MEK inhibitors are less susceptible to differences in MEK's activation state and do not drive the compensatory activation of MEK that could limit efficacy. Innovations in targeting ERK originate from dual inhibitors that block MEK-catalyzed ERK phosphorylation, thereby limiting the extent of ERK reactivation following feedback relief. Summary The primary goal in RAF, MEK and ERK inhibitors' development is to produce molecules with less inhibitor paradox and off-target effects, giving robust and sustained MAPK pathway inhibition.
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