The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis

Luisana Astudillo; Thiago G Da Silva; Zhiqiang Wang; Xiaoqing Han; Ke Jin; Jeffrey VanWye; Xiaoxia Zhu; Kelly Weaver; Taiji Oashi; Pedro E M Lopes; Darren Orton; Leif R Neitzel; Ethan Lee; Ralf Landgraf; David J Robbins; Alexander D MacKerell, Jr; Anthony J Capobianco

doi:10.1158/0008-5472.CAN-16-0061

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The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis

Journal article

Open access

Peer reviewed

The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis

Luisana Astudillo, Thiago G Da Silva, Zhiqiang Wang, Xiaoqing Han, Ke Jin, Jeffrey VanWye, Xiaoxia Zhu, Kelly Weaver, Taiji Oashi, Pedro E M Lopes, …

Cancer research (Chicago, Ill.), Vol.76(12), pp.3593-3603

2016-06-15

DOI: https://doi.org/10.1158/0008-5472.CAN-16-0061

PMCID: PMC4911243

PMID: 27197169

Abstract

DNA-Binding Proteins - metabolism

Transcription Factors - metabolism

Receptors, Notch - antagonists & inhibitors

Somites - embryology

Animals

Humans

Transcriptional Activation - drug effects

Cell Line, Tumor

Zebrafish

Mice

Thiazolidines - pharmacology

Neoplasms - drug therapy

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.

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.108 Molecular & Cell Biology - Cancer & Development; 1.108.579 Drosophila
Web Of Science research areas: Oncology
ESI research areas: Clinical Medicine

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Title: The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis
Creators: Luisana Astudillo - 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
Thiago G Da Silva - 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
Zhiqiang Wang - 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
Xiaoqing Han - 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
Ke Jin - 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
Jeffrey VanWye - 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
Xiaoxia Zhu - 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
Kelly Weaver - 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
Taiji Oashi - Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland
Pedro E M Lopes - Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland
Darren Orton - StemSynergy Therapeutics, Inc., Miami, Florida
Leif R Neitzel - Department of Cell and Developmental Biology and Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
Ethan Lee - Department of Cell and Developmental Biology and Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
Ralf Landgraf - Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida. Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida
David J Robbins - 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
Alexander D MacKerell, Jr - Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland
Anthony J Capobianco - 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
Publication Details: Cancer research (Chicago, Ill.), Vol.76(12), pp.3593-3603
Publisher: United States
Grant note: R01 CA125044 / NCI NIH HHS T32 HD007502 / NICHD NIH HHS R01 GM081635 / NIGMS NIH HHS R01 GM103926 / NIGMS NIH HHS R01 CA083736 / NCI NIH HHS
Academic Unit: Miller School of Medicine; Biochemistry & Molecular Biology Research; UMMG Department of Surgery; UMMG Dept of Surgery - Div of Surgical Oncology
Language: English
Resource Type: Journal article
PMID: 27197169
PMCID: PMC4911243
Record Identifier: 991031561110402976