Department of Chemistry & Biochemistry, College of Science and Mathematics, Rowan University, Glassboro, NJ, USA.
Department of Chemistry & Biochemistry, College of Science and Mathematics, Rowan University, Glassboro, NJ, USA.
Curr Opin Chem Biol. 2022 Dec;71:102205. doi: 10.1016/j.cbpa.2022.102205. Epub 2022 Sep 5.
The role of BRAF in tumor initiation has been established, however, the precise mechanism of autoinhibition has only been illustrated recently by several structural studies. These structures uncovered the basis by which the regulatory domains engage in regulating the activity of BRAF kinase domain, which lead to a more complete picture of the regulation cycle of RAF kinases. Small molecule BRAF inhibitors developed specifically to target BRAF have proven effective at inhibiting the most dominant BRAF mutant in melanomas, but are less potent against other BRAF mutants in RAS-driven diseases due to paradoxical activation of the MAPK pathway. A variety of new generation inhibitors that do not show paradoxical activation have been developed. Alternatively, efforts have begun to develop inhibitors targeting the dimer interface of BRAF. A deeper understanding of BRAF regulation together with more diverse BRAF inhibitors will be beneficial for drug development in RAF or RASdriven cancers.
BRAF 在肿瘤发生中的作用已经确立，然而，最近的几项结构研究才阐明了其自动抑制的精确机制。这些结构揭示了调节域结合以调节 BRAF 激酶结构域活性的基础，从而更完整地描绘了 RAF 激酶的调节循环。专门针对 BRAF 开发的小分子 BRAF 抑制剂已被证明可有效抑制黑色素瘤中最主要的 BRAF 突变体，但对 RAS 驱动疾病中的其他 BRAF 突变体的作用较弱，这是由于 MAPK 途径的反常激活。已经开发出多种不会表现出反常激活的新一代抑制剂。另外，已经开始努力开发针对 BRAF 二聚体界面的抑制剂。深入了解 BRAF 的调节以及更多种类的 BRAF 抑制剂将有助于 RAF 或 RAS 驱动的癌症的药物开发。
