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Research Articles: Therapeutics, Targets, and Development

Improved low molecular weight Myc-Max inhibitors

¹ Section of Hematology/Oncology, Children's Hospital of Pittsburgh; ² Department of Pharmacology, ³ The University of Pittsburgh Cancer Institute, and ⁴ Department of Molecular Genetics and Biochemistry, The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania and ⁵ Department of Chemistry, Georgetown University, Washington, District of Columbia

Requests for reprints: Edward V. Prochownik, Section of Hematology/Oncology, Children's Hospital of Pittsburgh, Rangos Research Center, Room 8125, 3460 Fifth Avenue, Pittsburgh, PA 15213. Phone: 412-692-6797; Fax: 412-692-5228. E-mail: procev{at}chp.edu

Abstract

Compounds that selectively prevent or disrupt the association between the c-Myc oncoprotein and its obligate heterodimeric partner Max (Myc-Max compounds) have been identified previously by high-throughput screening of chemical libraries. Although these agents specifically inhibit the growth of c-Myc–expressing cells, their clinical applicability is limited by their low potency. We describe here several chemical modifications of one of these original compounds, 10058-F4, which result in significant improvements in efficacy. Compared with the parent structure, these analogues show enhanced growth inhibition of c-Myc–expressing cells in a manner that generally correlates with their ability to disrupt c-Myc-Max association and DNA binding. Furthermore, we show by use of a sensitive fluorescence polarization assay that both 10058-F4 and its active analogues bind specifically to monomeric c-Myc. These studies show that improved Myc-Max compounds can be generated by a directed approach involving deliberate modification of an index compound. They further show that the compounds specifically target c-Myc, which exists in a dynamic and relatively unstructured state with only partial and transient -helical content. [Mol Cancer Ther 2007;6(9):2399–408]

Grant support: U.S. Department of Defense no. W81XWH-04-1-0226 and NIH grant CA105033 (E.V. Prochownik), Children's Hospital of Pittsburgh postdoctoral fellowship award (H. Wang), and American Cancer Society Institutional Research Grant Young Investigator Award and Georgetown University (S.J. Metallo).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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⁷ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁸ Unpublished data.

Received 1/ 4/07; revised 5/18/07; accepted 7/ 6/07.