American Association for Cancer Research
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Supplementary Figure Legends from The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis

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journal contribution
posted on 2023-03-31, 00:04 authored by 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, Anthony J. Capobianco

Description of the contents of supplementary figures 1, 2 and 3.




Training Program in Stem Cell and Regenerative Developmental Biology

Eunice Kennedy Shriver National Institute of Child Health and Human Development

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Samuel Waxman Cancer Research Foundation

UM/Sylvester Braman Family Breast Cancer Institute's Women's Cancer League Developmental

Dewitt Daughtry Family Department of Surgery and the Sylvester Comprehensive Cancer Center



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.