Department of Biochemistry and Department of Medicine, Albert Einstein Cancer Center , Albert Einstein College of Medicine , Bronx , New York 10461 , United States.
J Med Chem. 2018 Jul 26;61(14):5775-5793. doi: 10.1021/acs.jmedchem.7b01306. Epub 2018 Mar 6.
Oncogenic BRAF kinase deregulates the ERK signaling pathway in a large number of human tumors. FDA-approved BRAF inhibitors for BRAFV600E/K tumors have provided impressive clinical responses extending survival of melanoma patients. However, these drugs display paradoxical activation in normal tissue with BRAFWT due to RAF transactivation and priming, acquired drug resistance, and limited clinical effectiveness in non-V600 BRAF-dependent tumors, underscoring the urgent need to develop improved BRAF inhibitors. This review provides an overview of recent structural and biochemical insights into the mechanisms of BRAF regulation by BRAF inhibitors that are linked to their clinical activity, clinical liabilities, and medicinal chemistry properties. The effectiveness and challenges of structurally diverse next generation RAF inhibitors currently in preclinical and clinical development are discussed, along with mechanistic insights for developing more effective RAF inhibitors targeting different oncogenic BRAF conformations.
致癌 BRAF 激酶在大量人类肿瘤中使 ERK 信号通路失活。美国食品和药物管理局批准的用于 BRAFV600E/K 肿瘤的 BRAF 抑制剂为黑色素瘤患者的生存延长提供了令人印象深刻的临床反应。然而，由于 RAF 转激活和引发、获得性耐药以及非 V600 BRAF 依赖性肿瘤中临床效果有限，这些药物在 BRAFWT 的正常组织中显示出矛盾的激活，这突显了迫切需要开发改进的 BRAF 抑制剂。这篇综述概述了最近关于 BRAF 抑制剂调节 BRAF 的结构和生化见解，这些见解与它们的临床活性、临床局限性和药物化学特性有关。讨论了目前处于临床前和临床开发阶段的结构多样的下一代 RAF 抑制剂的有效性和挑战，以及针对不同致癌 BRAF 构象开发更有效的 RAF 抑制剂的机制见解。
