Improved low molecular weight Myc-Max inhibitors |
| |
Authors: | Wang Huabo Hammoudeh Dalia I Follis Ariele Viacava Reese Brian E Lazo John S Metallo Steven J Prochownik Edward V |
| |
Institution: | Section of Hematology/Oncology, Children's Hospital of Pittsburgh, Pittsburgh, PA 15213, USA. |
| |
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 alpha-helical content. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|