期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 23, 期 7, 页码 1386-1394出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.02.053
关键词
Dual inhibition; Akt; ERK; PI-3 Kinase; MEK1; MAP Kinase; Oncogenic signaling; KRAS; Driven oncogenesis
资金
- National Institutes of Health [P30CA046592, P01CA085878, P50CA093990, R01CA155198]
- NATIONAL CANCER INSTITUTE [P50CA093990, P01CA085878, R01CA155198, P30CA046592] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007315] Funding Source: NIH RePORTER
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 = 172 nM) and MEK1 (IC50 = 473 nM). 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. (C) 2015 Elsevier Ltd. All rights reserved.
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