使用双功能抑制剂对变构丝裂原活化蛋白激酶（MEK）和磷脂酰肌醇3激酶（PI3K）致癌靶点进行双重抑制。
Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor.
作者信息
Van Dort Marcian E, Galbán Stefanie, Wang Hanxiao, Sebolt-Leopold Judith, Whitehead Christopher, Hong Hao, Rehemtulla Alnawaz, Ross Brian D
机构信息
Center for Molecular Imaging, The University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA; Department of Radiology, The University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Center for Molecular Imaging, The University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA; Department of Radiation Oncology, The University of Michigan Medical School, Ann Arbor, MI 48109, USA.
出版信息
Bioorg Med Chem. 2015 Apr 1;23(7):1386-94. doi: 10.1016/j.bmc.2015.02.053. Epub 2015 Mar 6.
The MAP kinase (Ras/MEK/ERK) and PI3K/Akt/mTOR oncogenic signaling pathways are central regulators of KRAS-mediated transformation. Molecular reciprocity between the Ras/MEK/ERK and PI3K/Akt/mTOR pathways provides cancer cells with the ability to evade treatment when targeting only one pathway with monotherapy. Multi-kinase targeting was explored through the development of a single bivalent chemical entity by covalent linking of high-affinity MEK and PI3K inhibitors. A prototype dual-acting agent (compound 8) designed using the PI3K inhibitor ZSTK474 and the Raf/MEK inhibitor RO5126766 as scaffolds displayed high in vitro inhibition of both PI3K (IC50=172nM) and MEK1 (IC50=473nM). Additionally, compound 8 demonstrated significant modulation of MEK and PI3K signaling pathway activity in human A549 human lung adenocarcinoma cells and pancreatic cancer cells (PANC-1) and also decreased cellular viability in these two cell lines.
丝裂原活化蛋白激酶（Ras/MEK/ERK）和PI3K/Akt/mTOR致癌信号通路是KRAS介导的细胞转化的核心调节因子。Ras/MEK/ERK和PI3K/Akt/mTOR通路之间的分子相互作用使癌细胞在仅用单一疗法靶向其中一条通路时具有逃避治疗的能力。通过将高亲和力的MEK和PI3K抑制剂共价连接，开发出一种单一的二价化学实体，从而探索多激酶靶向作用。以PI3K抑制剂ZSTK474和Raf/MEK抑制剂RO5126766为支架设计的一种原型双效剂（化合物8）在体外对PI3K（IC50 = 172nM）和MEK1（IC50 = 473nM）均表现出高抑制作用。此外，化合物8在人A549人肺腺癌细胞和胰腺癌细胞（PANC - 1）中显示出对MEK和PI3K信号通路活性的显著调节，并且还降低了这两种细胞系中的细胞活力。
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