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.

[1]  G. Evan,et al.  Transcriptional activation by the human c-Myc oncoprotein in yeast requires interaction with Max , 1992, Nature.

[2]  G. Evan,et al.  The c‐Myc protein induces cell cycle progression and apoptosis through dimerization with Max. , 1993, The EMBO journal.

[3]  Bruno Amati,et al.  Oncogenic activity of the c-Myc protein requires dimerization with Max , 1993, Cell.

[4]  H. Yamada,et al.  Synthesis of 4-[1-(substituted phenyl)-2-oxo-pyrrolidin-4-yl]methyloxybenzoic acids and related compounds, and their inhibitory capacities toward fatty-acid and sterol biosyntheses , 1994 .

[5]  E. Prochownik,et al.  Differential apoptotic behaviors of c-myc, N-myc, and L-myc oncoproteins. , 1998, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[6]  Osman F. Güner,et al.  Pharmacophore perception, development, and use in drug design , 2000 .

[7]  P. Watkins,et al.  THE HUMAN CYP3A SUBFAMILY: PRACTICAL CONSIDERATIONS* , 2000, Drug metabolism reviews.

[8]  B. Amati.  Integrating Myc and TGF-β signalling in cell-cycle control , 2001, Nature Cell Biology.

[9]  B. Amati.  Integrating Myc and TGF-beta signalling in cell-cycle control. , 2001, Nature cell biology.

[10]  Christopher J. Oldfield,et al.  Intrinsically disordered protein. , 2001, Journal of molecular graphics & modelling.

[11]  Y. Martin,et al.  Do structurally similar molecules have similar biological activity? , 2002, Journal of medicinal chemistry.

[12]  D. Boger,et al.  Small-molecule antagonists of Myc/Max dimerization inhibit Myc-induced transformation of chicken embryo fibroblasts , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[13]  John S Lazo,et al.  Low molecular weight inhibitors of Myc–Max interaction and function , 2003, Oncogene.

[14]  R. Didziapetris,et al.  Fragmental methods in the analysis of biological activities of diverse compound sets. , 2003, Mini reviews in medicinal chemistry.

[15]  E. Prochownik.  c-Myc as a therapeutic target in cancer , 2004, Expert review of anticancer therapy.

[16]  J. Irwin,et al.  ZINC ? A Free Database of Commercially Available Compounds for Virtual Screening. , 2005 .

[17]  E. Prochownik,et al.  C-Myc-independent restoration of multiple phenotypes by two C-Myc target genes with overlapping functions. , 2005, Cancer research.

[18]  J. P. Kennedy,et al.  Evaluation of "credit card" libraries for inhibition of HIV-1 gp41 fusogenic core formation. , 2006, Journal of combinatorial chemistry.

[19]  Dirk Eick,et al.  Selective inhibition of c-Myc/Max dimerization and DNA binding by small molecules. , 2006, Chemistry & biology.

[20]  Robert D. Clark,et al.  A marriage made in torsional space: using GALAHAD models to drive pharmacophore multiplet searches , 2007, J. Comput. Aided Mol. Des..

[21]  Ruili Huang,et al.  Evaluating Chemical Structure Similarity as an Indicator of Cellular Growth Inhibition , 2006, J. Chem. Inf. Model..

[22]  Peter Willett,et al.  GALAHAD: 1. Pharmacophore identification by hypermolecular alignment of ligands in 3D , 2006, J. Comput. Aided Mol. Des..

[23]  Ruili Huang,et al.  Anticancer medicines in development: assessment of bioactivity profiles within the National Cancer Institute anticancer screening data , 2007, Molecular Cancer Therapeutics.

[24]  John S Lazo,et al.  Improved low molecular weight Myc-Max inhibitors , 2007, Molecular Cancer Therapeutics.

[25]  Christopher L. McClendon,et al.  Reaching for high-hanging fruit in drug discovery at protein–protein interfaces , 2007, Nature.

[26]  G. Evan,et al.  Modelling Myc inhibition as a cancer therapy , 2008, Nature.

[27]  E. Prochownik,et al.  Efficacy, pharmacokinetics, tisssue distribution, and metabolism of the Myc–Max disruptor, 10058-F4 [Z,E]-5-[4-ethylbenzylidine]-2-thioxothiazolidin-4-one, in mice , 2009, Cancer Chemotherapy and Pharmacology.

[28]  Christopher J. Oldfield,et al.  Intrinsically disordered proteins in human diseases: introducing the D2 concept. , 2008, Annual review of biophysics.

[29]  Robert D. Clark,et al.  Using a staged multi-objective optimization approach to find selective pharmacophore models , 2009, J. Comput. Aided Mol. Des..