Abstract：
Protein kinases (PKs) including RAF, perform a principal role in regulating countless cellular events such as cell growth, differentiation, and angiogenesis. Overexpression and mutation of RAF kinases are significant contributors to the development and spread of cancer. Therefore, RAF kinase inhibitors show promising outcomes as anti-cancer small molecules by suppressing the expression of RAF protein, blocking RAS/RAF interaction, or inhibiting RAF enzymes. Currently, there are insufficient reports about approving drugs with minimal degree of toxicity. Therefore, it is an urgent need to develop new RAF kinase inhibitors correlated with increased anticancer activity and lower cytotoxicity. This review outlines reported RAF kinase inhibitors for cancer treatment in patents and literature from 2019 to 2023. It highlights the available inhibitors by shedding light on their chemical structures, biochemical profiles, and current status. Additionally, we highlighted the hinge region-binding moiety of the reported compounds by showing the hydrogen bond patterns of representative inhibitors with the hinge region for each class. In recent years, RAF kinase inhibitors have gained considerable attention in cancer research and drug development due to their potential to be studied under clinical trials and their demonstration of various degrees of efficacy and safety profiles across different cancer types. However, addressing challenges related to drug resistance and safety represents a major avenue for the optimization and enhancement of RAF kinase inhibitors. Strategies to overcome such obstacles were discussed such as developing novel pan-RAF inhibitors, RAF dimer inhibitors, and combination treatments.
摘要：
蛋白激酶（PKs）包括RAF，在调节无数细胞事件如细胞生长中发挥主要作用，分化,和血管生成。RAF激酶的过表达和突变是癌症发展和扩散的重要因素。因此,RAF激酶抑制剂通过抑制RAF蛋白的表达作为抗癌小分子显示出有希望的结果，阻止RAS/RAF相互作用，或抑制RAF酶。目前,关于批准毒性程度最低的药物的报告不足。因此,迫切需要开发与增加抗癌活性和降低细胞毒性相关的新型RAF激酶抑制剂。这篇综述概述了2019年至2023年专利和文献中报道的用于癌症治疗的RAF激酶抑制剂。它通过照亮它们的化学结构来突出可用的抑制剂，生化概况,和当前状态。此外,我们通过显示每一类具有铰链区的代表性抑制剂的氢键模式,突出了所报道化合物的铰链区结合部分.近年来,RAF激酶抑制剂在癌症研究和药物开发中获得了相当大的关注，因为它们有可能在临床试验中进行研究，并且它们在不同癌症类型中具有不同程度的功效和安全性。然而,解决与耐药性和安全性相关的挑战是优化和增强RAF激酶抑制剂的主要途径。讨论了克服这些障碍的策略，例如开发新的泛RAF抑制剂，RAF二聚体抑制剂,和组合治疗。
