title: Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor.
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 (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.
authors.affiliation: 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.
authors.forename: Marcian E
authors.initials: ME
authors.lastname: Van Dort
authors.affiliation: 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.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Galbán
authors.affiliation: Center for Molecular Imaging, The University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA; Cellular and Molecular Biology Program, The University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Hanxiao
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Judith
authors.initials: J
authors.lastname: Sebolt-Leopold
authors.affiliation: 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.
authors.forename: Christopher
authors.initials: C
authors.lastname: Whitehead
authors.affiliation: 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.
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
authors.affiliation: 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; Department of Radiation Oncology, The University of Michigan Medical School, Ann Arbor, MI 48109, USA; Cellular and Molecular Biology Program, The University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Alnawaz
authors.initials: A
authors.lastname: Rehemtulla
authors.affiliation: 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; Department of Biological Chemistry, The University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: bdross@umich.edu.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D003374:Coumarins / Q000008:administration & dosage / Q000737:chemistry; D018360:Crystallography, X-Ray; D016503:Drug Delivery Systems / Q000379:methods*; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000737:chemistry*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014227:Triazines / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D003374:Coumarins; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; C577924:RO5126766; D014227:Triazines; C510150:ZSTK474; D058539:Phosphatidylinositol 3-Kinase; D048369:MAP Kinase Kinase 1
keywords: Akt; Driven oncogenesis; Dual inhibition; ERK; KRAS; MAP Kinase; MEK1; Oncogenic signaling; PI-3 Kinase