Discovery of Bifunctional Oncogenic Target Inhibitors against Allosteric Mitogen-Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-Kinase (PI3K)

Article abstract of DOI:10.1021/acs.jmedchem.5b01655

The synthesis of a series of single entity, bifunctional MEK1/PI3K inhibitors achieved by covalent linking of structural analogs of the ATP-competitive PI3K inhibitor ZSTK474 and the ATP-noncompetitive MEK inhibitor PD0325901 is described. Inhibitors displayed potent in vitro inhibition of MEK1 (0.015 < IC₅₀ (nM) < 56.7) and PI3K (54 < IC₅₀ (nM) < 341) in enzymatic inhibition assays. Concurrent MEK1 and PI3K inhibition was demonstrated with inhibitors 9 and 14 in two tumor cell lines (A549, D54). Inhibitors produced dose-dependent decreased cell viability similar to the combined administration of equivalent doses of ZSTK474 and PD0325901. In vivo efficacy of 14 following oral administration was demonstrated in D54 glioma and A549 lung tumor bearing mice. Compound 14 showed a 95% and 67% inhibition of tumor ERK1/2 and Akt phosphorylation, respectively, at 2 h postadministration by Western blot analysis, confirming the bioavailability and efficacy of this bifunctional inhibitor strategy toward combined MEK1/PI3K inhibition.

Full text of DOI:10.1021/acs.jmedchem.5b01655

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Article
Discovery of Bifunctional Oncogenic Target Inhibitors
against Allosteric Mitogen-Activated Protein Kinase
(MEK1) and Phosphatidylinositol 3-Kinase (PI3K)
Marcian E. Van Dort , Hao Hong , Hanxiao Wang, Charles A. Nino,
Rachel L. Lombardi , Avery E. Blanks, Stefanie Galbán, and Brian D Ross
J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.5b01655 • Publication Date (Web): 04 Mar 2016
Downloaded from http://pubs.acs.org on March 6, 2016
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Discovery of Bifunctional Oncogenic Target Inhibitors
against Allosteric Mitogen-Activated Protein Kinase (MEK1)
and Phosphatidylinositol 3-Kinase (PI3K)
Journal: Journal of Medicinal Chemistry
Manuscript ID jm-2015-016556.R4
Manuscript Type: Article
Date Submitted by the Author: 02-Mar-2016
Complete List of Authors: Van Dort , Marcian; University of Michigan , Radiology
Hong , Hao; University of Michigan , Radiology
Wang, Hanxiao; University of Michigan , Radiology
Nino, Charles ; University of Michigan , Radiology
Lombardi , Rachel ; University of Michigan , Radiology
Blanks, Avery; University of Michigan , Radiology
Galbán, Stefanie ; University of Michigan, Radiology
Ross, Brian; University of Michigan, Radiology
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Discovery of Bifunctional Oncogenic Target Inhibitors against Allosteric Mitogen-
Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-Kinase (PI3K)
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Marcian E. Van Dort†,‡, Hao Hong†,‡, Hanxiao Wang†,‡, Charles A. Nino†,‡, Rachel L.
Lombardi†,‡, Avery E. Blanks†,‡, Stefanie Galbán†,‡ and Brian D. Ross†,‡,ǁ,*
†Center for Molecular Imaging, ‡Department of Radiology, ǁDepartment of Biological Chemistry,
The University of Michigan Medical School, Ann Arbor, MI 48109
*Corresponding Author
Brian D. Ross
University of Michigan,
Center for Molecular Imaging
Departments of Radiology and Biological Chemistry
109 Zina Pitcher Place, Ann Arbor MI 48109-2200 USA.
Email: bdross@umich.edu
Phone: 734-763-2099
Fax: 734-763-5447
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ABSTRACT
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The synthesis of a series of single entity, bifunctional MEK1/PI3K inhibitors achieved by
covalent linking of structural analogs of the ATP-competitive PI3K inhibitor ZSTK474 and the
ATP-noncompetitive MEK inhibitor PD0325901 is described. Inhibitors displayed potent in
vitro inhibition of MEK1 (0.015 < IC50 (nM) < 56.7) and PI3K (54 < IC50 (nM) < 341) in
enzymatic inhibition assays. Concurrent MEK1 and PI3K inhibition was demonstrated with
inhibitors 9 and 14 in two tumor cell lines (A549, D54). Inhibitors produced dose-dependent
decreased cell viability similar to the combined administration of equivalent doses of ZSTK474
and PD0325901. In vivo efficacy of 14 following oral administration was demonstrated in a D54
glioma tumor bearing mouse. Compound 14 showed a 95% and 67% inhibition of tumor ERK1/2
and Akt phosphorylation, respectively, at 2 h post-administration by western blot analysis
confirming the bioavailability and efficacy of this bifunctional inhibitor strategy towards
combined MEK1/PI3K inhibition.
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INTRODUCTION
The Ras/MEK/ERK and PI3K/Akt/mTor pathways play a central role in the regulation of normal
cell growth, division and differentiation. Dysregulation of these signaling pathways driven by
oncogenic mutations/activation leading to elevated kinase activity has been demonstrated in
many human cancers including leukemia, melanoma, breast, ovarian, brain, lung and prostate
cancer. Strong evidence suggests the existence of a link (feedback loop) and crosstalk between
these two signaling cascades leading to redundancy in survival pathways 1-7. Consequently,
monotherapy targeting a single cascade may be insufficient to induce tumor cell death due to
drug resistance mechanisms. Additionally, many in vitro and in vivo studies have shown
synergistic outcomes in tumor cell death by simultaneous - inhibition of these two pathways 8-10
.
As the Ras/MEK/ERK and PI3K/Akt/mTor pathways are regulated by different mechanisms,
simultaneous co-targeting of these pathways is an attractive anticancer strategy. Current
approaches towards multi-kinase drug targeting involve drug administration as either (a) two or
more therapeutics (drug cocktail) or (b) a polyfunctional multi-targeting single agent therapeutic.
Our effort towards development of a bifunctional anticancer therapeutic for –simultaneous
inhibition of these two key signaling pathways has focused on the latter approach. Known
limitations of the drug cocktail approach include dissimilar toxicity profiles and
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