Discovery of novel Myc-Max heterodimer disruptors with a three-dimensional pharmacophore model.
A three-dimensional pharmacophore model was generated utilizing a set of known inhibitors of c-Myc-Max heterodimer formation. The model successfully identified a set of structurally diverse compounds with potential inhibitory activity against c-Myc. Nine compounds were tested in vitro, and four displayed affinities in the micromolar range and growth inhibitory activity against c-Myc-overexpressing cells. These studies demonstrate the applicability of pharmacophore modeling to the identification of novel and potentially more puissant inhibitors of the c-Myc oncoprotein.
Mustata
Gabriela
G
Department of Computational Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. gmustata@pitt.edu
Follis
Ariele Viacava
AV
Hammoudeh
Dalia I
DI
Metallo
Steven J
SJ
Wang
Huabo
H
Prochownik
Edward V
EV
Lazo
John S
JS
Bahar
Ivet
I
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D055786:Gene Knockout Techniques; D018922:HL-60 Cells; D025742:HMGA1b Protein / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D055503:Protein Multimerization; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001572:Benzofurans; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D011759:Pyrrolidines; D013844:Thiazoles; D025742:HMGA1b Protein