Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor. Issue 7 (1st April 2015)

• Record Type: Journal Article
• Authors: Van Dort, Marcian E.; Galbán, Stefanie; Wang, Hanxiao; Sebolt-Leopold, Judith; Whitehead, Christopher; Hong, Hao; Rehemtulla, Alnawaz; Ross, Brian D.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 7(2015)
• Page Start: 1386
• Page End: 1394
• Publication Date: 2015-04-01
• Subjects: Dual inhibition -- Akt -- ERK -- PI-3 Kinase -- MEK1 -- MAP Kinase -- Oncogenic signaling -- KRAS -- Driven oncogenesis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.02.053
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 (compound8 ) 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, compound8 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.