title: Reversible linkage of two distinct small molecule inhibitors of Myc generates a dimeric inhibitor with improved potency that is active in myc over-expressing cancer cell lines.
abstract: We describe the successful application of a novel approach for generating dimeric Myc inhibitors by modifying and reversibly linking two previously described small molecules. We synthesized two directed libraries of monomers, each comprised of a ligand, a connector, and a bioorthogonal linker element, to identify the optimal dimer configuration required to inhibit Myc. We identified combinations of monomers, termed self-assembling dimeric inhibitors, which displayed synergistic inhibition of Myc-dependent cell growth. We confirmed that these dimeric inhibitors directly bind to Myc blocking its interaction with Max and affect transcription of MYC dependent genes. Control combinations that are unable to form a dimer do not show any synergistic effects in these assays. Collectively, these data validate our new approach to generate more potent and selective inhibitors of Myc by self-assembly from smaller, lower affinity components. This approach provides an opportunity for developing novel therapeutics against Myc and other challenging protein:protein interaction (PPI) target classes.
authors: Coferon Inc, 25 Health Sciences Drive, Stony Brook, New York, United States of America.
authors: Jutta
authors: J
authors: Wanner
authors: Coferon Inc, 25 Health Sciences Drive, Stony Brook, New York, United States of America.
authors: Darlene
authors: D
authors: Romashko
authors: Coferon Inc, 25 Health Sciences Drive, Stony Brook, New York, United States of America.
authors: Douglas S
authors: DS
authors: Werner
authors: Coferon Inc, 25 Health Sciences Drive, Stony Brook, New York, United States of America.
authors: Earl W
authors: EW
authors: May
authors: Coferon Inc, 25 Health Sciences Drive, Stony Brook, New York, United States of America.
authors: Yue
authors: Y
authors: Peng
authors: Coferon Inc, 25 Health Sciences Drive, Stony Brook, New York, United States of America.
authors: Ryan
authors: R
authors: Schulz
authors: Coferon Inc, 25 Health Sciences Drive, Stony Brook, New York, United States of America.
authors: Kenneth W
authors: KW
authors: Foreman
authors: Coferon Inc, 25 Health Sciences Drive, Stony Brook, New York, United States of America.
authors: Suzanne
authors: S
authors: Russo
authors: Coferon Inc, 25 Health Sciences Drive, Stony Brook, New York, United States of America.
authors: Lee D
authors: LD
authors: Arnold
authors: Coferon Inc, 25 Health Sciences Drive, Stony Brook, New York, United States of America.
authors: Maneesh
authors: M
authors: Pingle
authors: Purdue University, West Lafayette, Indiana, United States of America.
authors: Donald E
authors: DE
authors: Bergstrom
authors: Department of Microbiology, Weill Cornell Medical College, New York, New York, United States of America.
authors: Francis
authors: F
authors: Barany
authors: Coferon Inc, 25 Health Sciences Drive, Stony Brook, New York, United States of America.
authors: Stuart
authors: S
authors: Thomson
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006018:Glycols / Q000737:chemistry; D006801:Humans; D008024:Ligands; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D060066:Protein Interaction Maps / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D054852:Small Molecule Libraries / Q000008:administration & dosage
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D006018:Glycols; D008024:Ligands; C499330:MAX protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D054852:Small Molecule Libraries