StemSynergy Therapeutics’ Notch1-Selective Small Molecule Inhibitor Prevents Tumor Growth by Ablation of Cancer Stem Cells

“The Notch pathway is an extremely attractive target for cancer therapeutics, as it is a critical driver of many human cancers. However, several approaches have failed to inhibit Notch safely in clinical trials and progress has nearly stagnated over the last few decades,” said Anthony J. Capobianco, Ph.D., corresponding author of the study. “To date, there are no inhibitors that directly target the intracellular Notch pathway with any significant specificity, which is central to safety in humans. Pharma has been trying to target this pathway for more than 20 years and this is the first example of a targeted therapeutic specific for Notch1 that has robust efficacy and minimal toxicity in human-derived malignant tumors models.”

In this study, the team of scientists refined their previous proof-of-concept inhibitor using computer modeling and experimental validation to identify chemical compounds that are selective for the Notch1 transcriptional complex. The lead compound, NADI-351, potently disrupts the formation of the Notch1 transcriptional complex which prevents transcription of oncogenic target genes and inhibits the growth of Notch1-dependent cancer cells and tumors.

Further validation confirmed NADI-351 is selective against Notch1 and against cancer stem cells, which require Notch1 activity. This mechanism was observed in multiple in vitro cancer models and replicated in NADI-351-treated human tumors in mice. “Our analysis confirms NADI-351 selectively disrupts Notch1-dependent transcription and that this mechanism has powerful downstream effects on cancer,” said Annamil Alvarez-Trotta, Ph.D., first author on the study. “Specifically, NADI-351 clears cancer stem cells by starving them of Notch signaling and causes cell death in tumors, including esophageal and triple-negative breast cancer. ”

Most importantly, NADI-351 does not induce the gastrointestinal toxicity which has long hampered development of Notch pathway inhibitors. The key to this therapeutic window is in the selective inhibition of the Notch1 transcriptional complex, while sparing those of other Notch proteins. “It’s likely that this selectivity, along with the short ‘pulse’ of inhibition that small molecules achieve, allows us to preferentially inhibit tumors addicted to Notch1 signaling without causing toxicity in tissues dependent on Notch signaling more generally,” noted William Guerrant, Ph.D., Senior Scientist at StemSynergy Therapeutics.

“We feel this new class of Notch1 inhibitors could be a game-changer for patients with Notch-dependent tumors and those that are highly resistant due to cancer stem cell activity,” said Capobianco, who is also a co-founder and President of StemSynergy Therapeutics. At the same time this breakthrough science is being published, StemSynergy Therapeutics is developing this class of compound for clinical evaluation. “We plan on aggressively pushing this through preclinical development and into cancer patients as a high priority and hope to be in clinical trials in the near term.”

About StemSynergy

StemSynergy Therapeutics is a pharmaceutical company focused on the discovery and development of novel small-molecule drugs that target developmental pathways fundamental to cancer. Our mission is to optimize efficacy against the pathways required to drive cancer stem cells, such as the Wnt, Sonic Hedgehog and Notch signaling pathways. For more information, visit www.stemsynergy.com.

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