Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, U.K.
Biochem Soc Trans. 2021 Feb 26;49(1):237-251. doi: 10.1042/BST20200485.
The RAS-regulated RAF-MEK1/2-ERK1/2 pathway promotes cell proliferation and survival and RAS and BRAF proteins are commonly mutated in cancer. This has fuelled the development of small molecule kinase inhibitors including ATP-competitive RAF inhibitors. Type I and type I½ ATP-competitive RAF inhibitors are effective in BRAFV600E/K-mutant cancer cells. However, in RAS-mutant cells these compounds instead promote RAS-dependent dimerisation and paradoxical activation of wild-type RAF proteins. RAF dimerisation is mediated by two key regions within each RAF protein; the RKTR motif of the αC-helix and the NtA-region of the dimer partner. Dimer formation requires the adoption of a closed, active kinase conformation which can be induced by RAS-dependent activation of RAF or by the binding of type I and I½ RAF inhibitors. Binding of type I or I½ RAF inhibitors to one dimer partner reduces the binding affinity of the other, thereby leaving a single dimer partner uninhibited and able to activate MEK. To overcome this paradox two classes of drug are currently under development; type II pan-RAF inhibitors that induce RAF dimer formation but bind both dimer partners thus allowing effective inhibition of both wild-type RAF dimer partners and monomeric active class I mutant RAF, and the recently developed "paradox breakers" which interrupt BRAF dimerisation through disruption of the αC-helix. Here we review the regulation of RAF proteins, including RAF dimers, and the progress towards effective targeting of the wild-type RAF proteins.
RAS 调节的 RAF-MEK1/2-ERK1/2 通路促进细胞增殖和存活，RAS 和 BRAF 蛋白在癌症中通常发生突变。这推动了小分子激酶抑制剂的发展，包括 ATP 竞争性 RAF 抑制剂。I 型和 I½ 型 ATP 竞争性 RAF 抑制剂在 BRAFV600E/K 突变型癌细胞中有效。然而，在 RAS 突变细胞中，这些化合物反而促进了 RAS 依赖性二聚化和野生型 RAF 蛋白的反常激活。RAF 二聚化由每个 RAF 蛋白内的两个关键区域介导；αC 螺旋的 RKTR 基序和二聚体伴侣的 NtA 区域。二聚体形成需要采用封闭的、活性激酶构象，这可以通过 RAF 的 RAS 依赖性激活或 I 型和 I½ 型 RAF 抑制剂的结合来诱导。I 型或 I½ 型 RAF 抑制剂与一个二聚体伴侣的结合降低了另一个二聚体伴侣的结合亲和力，从而使单个二聚体伴侣未被抑制并能够激活 MEK。为了克服这种悖论，目前正在开发两类药物；诱导 RAF 二聚化但结合两个二聚体伴侣的 II 型泛 RAF 抑制剂，从而允许有效抑制野生型 RAF 二聚体伴侣和单体活性 I 型突变 RAF，以及最近开发的“悖论破坏者”，它们通过破坏 αC 螺旋来中断 BRAF 二聚化。本文综述了 RAF 蛋白（包括 RAF 二聚体）的调节以及有效靶向野生型 RAF 蛋白的进展。
