title: The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis.
abstract: In many cancers, aberrant Notch activity has been demonstrated to play a role in the initiation and maintenance of the neoplastic phenotype and in cancer stem cells, which may allude to its additional involvement in metastasis and resistance to therapy. Therefore, Notch is an exceedingly attractive therapeutic target in cancer, but the full range of potential targets within the pathway has been underexplored. To date, there are no small-molecule inhibitors that directly target the intracellular Notch pathway or the assembly of the transcriptional activation complex. Here, we describe an in vitro assay that quantitatively measures the assembly of the Notch transcriptional complex on DNA. Integrating this approach with computer-aided drug design, we explored potential ligand-binding sites and screened for compounds that could disrupt the assembly of the Notch transcriptional activation complex. We identified a small-molecule inhibitor, termed Inhibitor of Mastermind Recruitment-1 (IMR-1), that disrupted the recruitment of Mastermind-like 1 to the Notch transcriptional activation complex on chromatin, thereby attenuating Notch target gene transcription. Furthermore, IMR-1 inhibited the growth of Notch-dependent cell lines and significantly abrogated the growth of patient-derived tumor xenografts. Taken together, our findings suggest that a novel class of Notch inhibitors targeting the transcriptional activation complex may represent a new paradigm for Notch-based anticancer therapeutics, warranting further preclinical characterization. Cancer Res; 76(12); 3593-603. ©2016 AACR.
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, Florida. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Luisana
authors.initials: L
authors.lastname: Astudillo
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, Florida. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Thiago G
authors.initials: TG
authors.lastname: Da Silva
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, Florida. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, Florida. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Han
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, Florida. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Ke
authors.initials: K
authors.lastname: Jin
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, Florida. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: VanWye
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, Florida. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, Florida. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Kelly
authors.initials: K
authors.lastname: Weaver
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland.
authors.forename: Taiji
authors.initials: T
authors.lastname: Oashi
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland.
authors.forename: Pedro E M
authors.initials: PE
authors.lastname: Lopes
authors.affiliation: StemSynergy Therapeutics, Inc., Miami, Florida.
authors.forename: Darren
authors.initials: D
authors.lastname: Orton
authors.affiliation: Department of Cell and Developmental Biology and Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Leif R
authors.initials: LR
authors.lastname: Neitzel
authors.affiliation: Department of Cell and Developmental Biology and Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Ethan
authors.initials: E
authors.lastname: Lee
authors.affiliation: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida. Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida.
authors.forename: Ralf
authors.initials: R
authors.lastname: Landgraf
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, Florida. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: David J
authors.initials: DJ
authors.lastname: Robbins
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
authors.affiliation: Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, Florida. Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida. tcapobianco@med.miami.edu.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Capobianco
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*; D019170:Somites / Q000196:embryology; D053778:Thiazolidines / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects*; D015027:Zebrafish
chemical_list: D004268:DNA-Binding Proteins; C000621821:IMR-1 compound; C430872:MAML1 protein, human; D051880:Receptors, Notch; D053778:Thiazolidines; D014157:Transcription Factors