Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity.
Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity.
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DOI：
10.1158/0008-5472.can-12-3937
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发表时间：
2013-07-01
期刊：
影响因子：
11.2
通讯作者：
Sakai T
中科院分区：
文献类型：
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作者：
Ishii N;Harada N;Joseph EW;Ohara K;Miura T;Sakamoto H;Matsuda Y;Tomii Y;Tachibana-Kondo Y;Iikura H;Aoki T;Shimma N;Arisawa M;Sowa Y;Poulikakos PI;Rosen N;Aoki Y;Sakai T
RAS突变的肿瘤通常依赖细胞外信号调节激酶(ERK)信号来生长；然而，MEK抑制剂在这些肿瘤中只有轻微的抗肿瘤活性。MEK抑制剂可解除ERK依赖的RAF反馈抑制，并导致MEK磷酸化的诱导。我们现在已经确定了一种MEK抑制剂CH5126766(RO5126766)，它也具有抑制RAF激酶的独特性质。CH5126766结合导致MEK采用一种构象，其中它不能被RAF磷酸化并从RAF释放。这导致了稳定的MEK/RAF复合体的形成和RAF激酶的抑制。与这一机制一致，该药物不会诱导MEK磷酸化。CH5126766比标准的MEK抑制剂更有效地抑制ERK信号的输出，后者诱导MEK磷酸化，并具有强大的抗肿瘤活性。这些结果表明，RAF反馈的缓解限制了标准MEK抑制剂对通路的抑制。CH5126766代表了一种新型的MEK抑制剂，它使MEK成为RAF的显性阴性抑制剂，这样做可能会增强对具有突变RAS的ERK依赖肿瘤的治疗活性。
Tumors with mutant RAS are often dependent on extracellular signal–regulated kinase (ERK) signaling for growth; however, MEK inhibitors have only marginal antitumor activity in these tumors. MEK inhibitors relieve ERK-dependent feedback inhibition of RAF and cause induction of MEK phosphorylation. We have now identified a MEK inhibitor, CH5126766 (RO5126766), that has the unique property of inhibiting RAF kinase as well. CH5126766 binding causes MEK to adopt a conformation in which it cannot be phosphorylated by and released from RAF. This results in formation of a stable MEK/RAF complex and inhibition of RAF kinase. Consistent with this mechanism, this drug does not induce MEK phosphorylation. CH5126766 inhibits ERK signaling output more effectively than a standard MEK inhibitor that induces MEK phosphorylation and has potent antitumor activity as well. These results suggest that relief of RAF feedback limits pathway inhibition by standard MEK inhibitors. CH5126766 represents a new type of MEK inhibitor that causes MEK to become a dominant-negative inhibitor of RAF and that, in doing so, may have enhanced therapeutic activity in ERK-dependent tumors with mutant RAS.