RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling.,Nature Medicine

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RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling.
Nature Medicine ( IF 58.7 ) Pub Date : 2018-Dec-17 , DOI: 10.1038/s41591-018-0274-5
Zhan Yao _{1,

2} , Yijun Gao ₁ , Wenjing Su ₁ , Rona Yaeger _{2,

3} , Jessica Tao ₂ , Na Na ₁ , Ying Zhang ₄ , Chao Zhang ₄ , Andrey Rymar ₄ , Anthony Tao ₅ , Neilawattie M Timaul ₁ , Rory Mcgriskin ₁ , Nathaniel A Outmezguine ₁ , HuiYong Zhao ₁ , Qing Chang ₁ , Besnik Qeriqi ₁ , Mariano Barbacid ₆ , Elisa de Stanchina ₁ , David M Hyman _{2,

3} , Gideon Bollag ₄ , Neal Rosen _{1,

2,

7}

Affiliation

Activating BRAF mutants and fusions signal as RAS-independent constitutively active dimers with the exception of BRAF V600 mutant alleles which can function as active monomers¹. Current RAF inhibitors are monomer selective, they potently inhibit BRAF V600 monomers but their inhibition of RAF dimers is limited by induction of negative cooperativity when bound to one site in the dimer^1-3. Moreover, acquired resistance to these drugs is usually due to molecular lesions that cause V600 mutants to dimerize^4-8. We show here that PLX8394, a new RAF inhibitor⁹, inhibits ERK signaling by specifically disrupting BRAF-containing dimers, including BRAF homodimers and BRAF-CRAF heterodimers, but not CRAF homodimers or ARAF-containing dimers. Differences in the amino acid residues in the amino (N)-terminal portion of the kinase domain of RAF isoforms are responsible for this differential vulnerability. As a BRAF-specific dimer breaker, PLX8394 selectively inhibits ERK signaling in tumors driven by dimeric BRAF mutants, including BRAF fusions and splice variants as well as BRAF V600 monomers, but spares RAF function in normal cells in which CRAF homodimers can drive signaling. Our work suggests that drugs with these properties will be safe and useful for treating tumors driven by activating BRAF mutants or fusions.

中文翻译：

RAF 抑制剂 PLX8394 选择性地破坏 BRAF 二聚体和 RAS 独立的 BRAF 突变驱动信号。

激活 BRAF 突变体和融合信号作为不依赖于 RAS 的组成型活性二聚体，但 BRAF V600 突变等位基因除外，它可以作为活性单体¹。目前的 RAF 抑制剂是单体选择性的，它们有效地抑制 BRAF V600 单体，但它们对 RAF 二聚体的抑制在结合到二聚体中的一个位点时受到负协同作用的诱导限制^1-3。此外，对这些药物的获得性耐药通常是由于导致 V600 突变体二聚化^4-8的分子损伤。我们在这里展示了 PLX8394，一种新的 RAF 抑制剂⁹, 通过特异性破坏含有 BRAF 的二聚体（包括 BRAF 同二聚体和 BRAF-CRAF 异二聚体，但不包括 CRAF 同二聚体或含有 ARAF 的二聚体）来抑制 ERK 信号。RAF 异构体激酶域的氨基 (N) 末端部分的氨基酸残基差异是造成这种差异脆弱性的原因。作为 BRAF 特异性二聚体阻断剂，PLX8394 选择性地抑制由二聚体 BRAF 突变体驱动的肿瘤中的 ERK 信号，包括 BRAF 融合和剪接变体以及 BRAF V600 单体，但保留 CRAF 同二聚体可以驱动信号的正常细胞中的 RAF 功能。我们的工作表明，具有这些特性的药物对于治疗由激活 BRAF 突变体或融合驱动的肿瘤是安全且有用的。

更新日期：2019-01-27

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