Oncology Central

Notch inhibitor effective against cancer cells for first time

Researchers from Sylvester Comprehensive Cancer Center at the University of Miami School of Medicine (SCCC; Miami, FL, USA) have identified a potential new class of personalized anticancer drugs. The team demonstrated for the first time that a small molecule inhibitor of the Notch pathway could suppress tumor growth, paving the way for a novel class of anticancer treatments.

“The Notch pathway is an exceedingly attractive therapeutic target in cancer, but the full range of potential targets within the pathway has been underexplored,” explained Anthony Capobianco (SCCC), senior author of the study, which was recently published in Cancer Research.

Capobianco continued: “To date, there are no small-molecule inhibitors that directly target the intracellular Notch pathway directly. We’ve been trying to target this pathway for more than15 years and this is the first example of a targeted therapeutic specific for Notch that has an effect on human-derived malignant tumors.”

Aberrant activity in the Notch pathway has been identified previously to contribute to the initiation and maintenance of cancer stem cells. The core of Notch activity is a complex of three proteins that mediates transcription processes vital for tumor cell survival.

The SCCC team, in collaboration with researchers at the Computer-Aided Drug Design (CADD) Center at the University of Maryland (MD, USA), utilized a computational drug discovery approach to identify the small molecule Notch inhibitor, termed IMR-1. IMR-1 disrupts recruitment of a transcriptional co-activator protein, MAML1, to the Notch complex, thus preventing transcription of Notch target genes.

“CADD offers the potential to identify therapeutic agents for challenging drug targets, including those involved in cancer,” commented Alex MacKerell, University of Maryland. “In this study, we were able to apply CADD to identify potential drug-binding sites on the previously uncharted Notch transcriptional complex and then screen more than one million drug-like compounds to identify those with a high probability of binding to the complex and blocking its function.”

“The success of this approach in identifying the novel Notch inhibitor emphasizes the utility of CADD in jump-starting research efforts toward the development of novel therapeutic approaches to the treatment of cancer and other diseases,” concluded MacKerell.

Importantly, the researchers demonstrated that IMR-1 has an effect on tumor growth. Administration of IMR-1 inhibited the growth of Notch-dependent cell lines and significantly suppressed the growth of patient-derived tumors in mouse xenograft studies.

“Our findings suggest that a novel class of Notch inhibitors targeting MAML1 may represent a new paradigm for Notch-based anticancer therapeutics,” concluded Capobianco. “As a next step, we plan on moving this laboratory research from human-derived disease models to cancer patients over the next years.”

Sources: Astudillo L, Da Silva TG, Wang Z et al. The small molecule IMR-1 inhibits the Notch transcriptional activation complex to suppress tumorigenesis. Cancer Res. 76(12), 35933603 (2016); http://sylvester.org/news/2016/06/sylvester-scientists-provide-proof-of-concept-for-potential-new-class-of-ca




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