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

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TitleThe Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis.
Publication TypeJournal Article
Year of Publication2016
AuthorsAstudillo, L, Da Silva, TG, Wang, Z, Han, X, Jin, K, VanWye, J, Zhu, X, Weaver, K, Oashi, T, Lopes, PEM, Orton, D, Neitzel, LR, Lee, E, Landgraf, R, Robbins, DJ, Mackerell, AD, Capobianco, AJ
JournalCancer Res
Volume76
Issue12
Pagination3593-603
Date Published2016 Jun 15
ISSN1538-7445
KeywordsAnimals, Cell Line, Tumor, DNA-Binding Proteins, Humans, Mice, Neoplasms, Receptors, Notch, Somites, Thiazolidines, Transcription Factors, Transcriptional Activation, Zebrafish
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.

DOI10.1158/0008-5472.CAN-16-0061
Alternate JournalCancer Res.
PubMed ID27197169
PubMed Central IDPMC4911243
Grant ListT32 HD007502 / HD / NICHD NIH HHS / United States
R01 GM103926 / GM / NIGMS NIH HHS / United States
R01 CA083736 / CA / NCI NIH HHS / United States
R01 GM081635 / GM / NIGMS NIH HHS / United States
R01 CA125044 / CA / NCI NIH HHS / United States