The RAF family kinases function in the RAS–ERK pathway to transmit signals from activated RAS to the downstream kinases MEK and ERK. This pathway regulates cell proliferation, differentiation and survival, enabling mutations in RAS and RAF to act as potent drivers of human cancers. Drugs targeting the prevalent oncogenic mutant BRAF(V600E) have shown great efficacy in the clinic, but long-term effectiveness is limited by resistance mechanisms that often exploit the dimerization-dependent process by which RAF kinases are activated. Here, we investigated a proteolysis-targeting chimera (PROTAC) approach to BRAF inhibition. The most effective PROTAC, termed P4B, displayed superior specificity and inhibitory properties relative to non-PROTAC controls in BRAF(V600E) cell lines. In addition, P4B displayed utility in cell lines harboring alternative BRAF mutations that impart resistance to conventional BRAF inhibitors. This work provides a proof of concept for a substitute to conventional chemical inhibition to therapeutically constrain oncogenic BRAF.

RAF 家族激酶在 RAS-ERK 通路中起作用，将信号从激活的 RAS 传递到下游激酶 MEK 和 ERK。该通路调节细胞增殖、分化和存活，使 RAS 和 RAF 中的突变成为人类癌症的有力驱动因素。针对流行的致癌突变体 BRAF (V600E) 的药物在临床上显示出巨大的疗效，但长期有效性受到耐药机制的限制，这些耐药机制通常利用 RAF 激酶被激活的二聚化依赖过程。在这里，我们研究了一种针对 BRAF 抑制的蛋白水解靶向嵌合体 (PROTAC) 方法。最有效的 PROTAC，称为 P4B，在BRAF中显示出优于非 PROTAC 对照的特异性和抑制特性(V600E) 细胞系。此外，P4B 在携带对常规 BRAF 抑制剂具有抗性的替代BRAF突变的细胞系中显示出效用。这项工作为替代传统化学抑制以治疗性限制致癌 BRAF 提供了概念证明。