Abstract
Abstract Deregulation of the Notch pathway underlies many aspects of cancer physiology depending on cell type and context. In many human cancers, aberrant Notch activity has been demonstrated to play a role in the initiation and maintenance of the neoplastic phenotype. Notch also plays a central role in cancer stem cells, which may underlie a role in metastasis and resistance to therapy. The important and diverse role played by Notch in cancer makes it an exceedingly attractive target for anti-neoplastic therapeutics. However, the full range of potential targets in the pathway have been under-explored. To date, there are no small molecule inhibitors that directly target the intracellular Notch pathway or the assembly of the transcriptional activation complex. We have developed an in vitro assay that quantitatively measures the assembly of the Notch transcriptional complex on DNA. Through 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. Herein we report the identification and characterization of a small molecule inhibitor of the Notch transcriptional activation complex, termed Inhibitor of Mastermind Recruitment-1 (IMR-1). We demonstrate that IMR-1 disrupts the recruitment of Mastermind-like 1 (Maml1) to the Notch transcriptional activation complex on chromatin and thereby causes a decrease in Notch target gene transcription. Furthermore, IMR-1 inhibits the growth of Notch-dependent cell lines and significantly abrogates the growth of patient-derived tumor xenografts. Therefore, our data suggest that a novel class of Notch inhibitors targeting the transcriptional activation complex may represent a new paradigm for Notch-based anticancer therapeutics. Citation Format: Luisana Astudillo, Anthony J. Capobianco. A small molecule inhibitor of the Notch transcriptional activation complex. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A39.