title: A credit-card library approach for disrupting protein-protein interactions.
abstract: Protein-protein interfaces are prominent in many therapeutically important targets. Using small organic molecules to disrupt protein-protein interactions is a current challenge in chemical biology. An important example of protein-protein interactions is provided by the Myc protein, which is frequently deregulated in human cancers. Myc belongs to the family of basic helix-loop-helix leucine zipper (bHLH-ZIP) transcription factors. It is biologically active only as heterodimer with the bHLH-ZIP protein Max. Herein, we report a new strategy for the disruption of protein-protein interactions that has been corroborated through the design and synthesis of a small parallel library composed of 'credit-card' compounds. These compounds are derived from a planar, aromatic scaffold and functionalized with four points of diversity. From a 285 membered library, several hits were obtained that disrupted the c-Myc-Max interaction and cellular functions of c-Myc. The IC50 values determined for this small focused library for the disruption of Myc-Max dimerization are quite potent, especially since small molecule antagonists of protein-protein interactions are notoriously difficult to find. Furthermore, several of the compounds were active at the cellular level as shown by their biological effects on Myc action in chicken embryo fibroblast assays. In light of our findings, this approach is considered a valuable addition to the armamentarium of new molecules being developed to interact with protein-protein interfaces. Finally, this strategy for disrupting protein-protein interactions should prove applicable to other families of proteins.
authors.affiliation: Department of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla CA 92037, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Jin
authors.initials: J
authors.lastname: Shi
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Jason A
authors.initials: JA
authors.lastname: Moss
authors.forename: Peter K
authors.initials: PK
authors.lastname: Vogt
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D002645:Chickens; D002942:Circular Dichroism; D015342:DNA Probes; D024202:Electrophoretic Mobility Shift Assay; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D015342:DNA Probes; C067850:Myc associated factor X; D016271:Proto-Oncogene Proteins c-myc