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.

中文翻译：

---

BRAF抑制剂在癌症中的最新见解

致癌的BRAF激酶可在大量人类肿瘤中解除ERK信号通路的调控。FDA批准的BRAFV600E / K肿瘤BRAF抑制剂提供了令人印象深刻的临床反应，延长了黑素瘤患者的生存期。然而，由于RAF的反式激活和引发，这些药物在BRAFWT的正常组织中显示出自相矛盾的激活，获得性耐药性以及在非V600 BRAF依赖性肿瘤中有限的临床有效性，强调了迫切需要开发改良的BRAF抑制剂。这篇综述概述了BRAF抑制剂调节BRAF机制的最新结构和生化见解，这些机理与其临床活性，临床责任和药物化学性质有关。