靶向BRAF二聚体界面的变构BRAF肽抑制剂的开发。,ACS Chemical Biology

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靶向BRAF二聚体界面的变构BRAF肽抑制剂的开发。
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-06-17 , DOI: 10.1021/acschembio.9b00191
Amber Y Gunderwala ₁ , Anushri A Nimbvikar ₁ , Nicholas J Cope ₁ , Zhijun Li ₁ , Zhihong Wang ₁

Affiliation

BRAF是人类癌症中最常见的突变激酶，并且是致癌RAS的主要效应物之一，使BRAF成为抗癌药物开发的重要目标。野生型BRAF和多种致癌BRAF突变体依赖于激酶结构域的二聚化，这也成为当前BRAF治疗的耐药性和副作用的元凶。因此，能够破坏BRAF二聚体的变构BRAF抑制剂可以消除由致癌BRAF或RAS驱动的超活化MAPK（促分裂原活化蛋白激酶）信号传导，并克服目前BRAF抑制剂的主要局限性。为了确定这一点，我们采用了计算机方法，设计了一系列针对BRAF二聚体界面的肽抑制剂。发现一种所得的抑制剂有效抑制BRAF同二聚体和异二聚体的激酶活性，包括致癌的BRAFG469A突变体。此外，该抑制剂与FDA批准的针对二聚体BRAF的，具有ATP竞争性的BRAF抑制剂具有协同作用，这表明变构BRAF抑制剂具有极大的潜力来扩展当前的BRAF疗法的应用。另外，靶向BRAF激酶的二聚体界面导致RAF和MEK的蛋白质降解，揭示了RAF在保护大的MAPK复合物免受蛋白质降解中的新型支架功能。总之，我们已经开发出了一种有效的铅肽抑制剂，可用于靶向BRAF在癌细胞中的二聚体界面。

"点击查看英文标题和摘要"

Development of Allosteric BRAF Peptide Inhibitors Targeting the Dimer Interface of BRAF.

BRAF is the most frequently mutated kinase in human cancers and is one of the major effectors of oncogenic RAS, making BRAF a target of considerable interest for anticancer drug development. Wild-type BRAF and a variety of oncogenic BRAF mutants are dependent on dimerization of the kinase domain, which also emerges as a culprit of drug resistance and side effects of current BRAF therapies. Thus, allosteric BRAF inhibitors capable of disrupting BRAF dimers could abrogate hyperactivated MAPK (mitogen-activated protein kinase) signaling driven by oncogenic BRAF or RAS and overcome the major limitations of current BRAF inhibitors. To establish this, we applied an in silico approach to design a series of peptide inhibitors targeting the dimer interface of BRAF. One resulting inhibitor was found to potently inhibit the kinase activity of BRAF homo- and heterodimers, including oncogenic BRAFG469A mutant. Moreover, this inhibitor synergizes with FDA-approved, ATP-competitive BRAF inhibitors against dimeric BRAF, suggesting that allosteric BRAF inhibitors have great potential to extend the application of current BRAF therapies. Additionally, targeting the dimer interface of BRAF kinase leads to protein degradation of both RAF and MEK, uncovering a novel scaffolding function of RAF in protecting large MAPK complexes from protein degradation. In conclusion, we have developed a potent lead peptide inhibitor for targeting the dimer interface of BRAF in cancer cells. The dual function of this peptide inhibitor validates the strategy for developing allosteric BRAF inhibitors that specifically dissociate RAF dimers and destabilize the MAPK signaling complex.

更新日期：2019-06-03

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