Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor

Marcian E Van Dort; Stefanie Galbán; Hanxiao Wang; Judith Sebolt-Leopold; Christopher Whitehead; Hao Hong; Alnawaz Rehemtulla; Brian D Ross

doi:10.1016/j.bmc.2015.02.053

Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor

Bioorg Med Chem. 2015 Apr 1;23(7):1386-94. doi: 10.1016/j.bmc.2015.02.053. Epub 2015 Mar 6.

Authors

Marcian E Van Dort¹, Stefanie Galbán², Hanxiao Wang³, Judith Sebolt-Leopold¹, Christopher Whitehead¹, Hao Hong¹, Alnawaz Rehemtulla⁴, Brian D Ross⁵

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.

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.

Keywords: Akt; Driven oncogenesis; Dual inhibition; ERK; KRAS; MAP Kinase; MEK1; Oncogenic signaling; PI-3 Kinase.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Allosteric Regulation / drug effects
Animals
Cell Line
Coumarins / administration & dosage
Coumarins / chemistry
Crystallography, X-Ray
Drug Delivery Systems / methods*
Enzyme Inhibitors / administration & dosage*
Enzyme Inhibitors / chemistry*
Humans
MAP Kinase Kinase 1 / antagonists & inhibitors*
MAP Kinase Kinase 1 / metabolism
Mice
Phosphatidylinositol 3-Kinase / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Protein Structure, Secondary
Protein Structure, Tertiary
Triazines / administration & dosage
Triazines / chemistry

Substances

Coumarins
Enzyme Inhibitors
Phosphoinositide-3 Kinase Inhibitors
RO5126766
Triazines
ZSTK474
Phosphatidylinositol 3-Kinase
MAP Kinase Kinase 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding