威罗菲尼
达布拉芬尼
MAPK/ERK通路
黑色素瘤
癌症研究
医学
索拉非尼
激酶
生物
转移性黑色素瘤
遗传学
肝细胞癌
作者
Ankit Kumar Singh,Adarsh Kumar,Suresh Thareja,Pradeep Kumar
出处
期刊:Anti-cancer Agents in Medicinal Chemistry
[Bentham Science]
日期:2023-02-01
卷期号:23 (3): 278-297
被引量:7
标识
DOI:10.2174/1871520622666220624164152
摘要
Melanomas represent only 4% of all skin cancers, but their mortality rate is more than 50 % of any other skin cancer. Alteration in genetic and environmental factors are the risk factors for melanoma development. The RAS/RAF/MEK/ERK or Mitogen-activated protein kinase (MAPK) pathway is activated in melanoma. BRAF activation is necessary to govern differentiation, proliferation, and survival. Mutations in BRAF were found in 80-90% of all melanomas. Over 90% of BRAF mutations occur at codon 600, and over 90% of them are BRAFV600E other common mutations are BRAFV600K, BRAFV600R, BRAF V600'E2', and BRAF V600D. Based on αC-helix and DFG motif (αC-helix-IN/DFG-IN), (αC-helix-IN/DFG-OUT), (αC-helix-OUT/DFG-IN) and (αC-helix-OUT/ DFG-OUT) are four structural types of inhibitors for targeting BRAF. Sorafenib, Vemurafenib, Dabrafenib, and Encorafenib are FDAapproved for the treatment of BRAF. Understanding melanoma pathogenesis, RAS/RAF/MEK/ERK or MAPK pathway, and BRAF conformations, mutations, the problems with FDA approved BRAF inhibitors will be important for new drug discovery, modification of existing BRAF barriers to improve target specific action, and prevent increasing response levels while minimizing toxicity.
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