Small Molecule Inhibitors of Notch Activation Complex Kinase (NACK) as Novel Cancer Therapeutic Agents

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ABSTRACT Aberrantly activated NOTCH signaling contributes to tumorigenesis in a range of cancer types, including esophageal adenocarcinoma (EAC), the incidence of which has tripled over the last 40 years with poor overall five-year survival. The Notch Activation Complex Kinase (NACK) is a co-activator of NOTCH signaling, and is often overexpressed in NOTCH-dependent cancers. Genetic depletion of NACK is effective in eradicating NOTCH-dependent EACs in pre-clinical models, suggesting that NACK is a promising therapeutic target for NOTCH-dependent cancers. Through a licensing agreement with University of Miami, we have obtained exclusive rights to develop small molecules targeting the NACK kinase domain (iNACKs), in order to treat NOTCH/NACK-dependent cancers. So far, we have developed several iNACKs that prevent NACK from being recruited to the NOTCH transcriptional complex, inhibit NOTCH pathway activation, and suppress the growth of NOTCH/NACK-dependent EAC in cell culture and in mice. Moreover, we show that our early lead iNACK does not elicit gastrointestinal track (GI) toxicity, which is often associated with NOTCH blockage by gamma secretase inhibitors. Therefore, we hypothesize that blockade of NOTCH signaling via inhibition of NACK will be safe and effective in NOTCH-dependent cancers. The goal of our proposal is to develop next-generation iNACKs, that are more potent, specific, and possess better drug-like properties. We propose two specific aims: A1. Develop iNACKs with improved potency, selectivity, and pharmacokinetic properties through Structure- Activity Relationship (SAR) studies. A2. Evaluate the drug-like properties and in vivo efficacy of SSTK-0388 and other iNACKs through ADMET, pharmacokinetics (PK), and mouse xenograft studies. These aims will establish up to two lead iNACK compounds for further development, including: (1) Efficacy in more human patient-derived xenografts and genetically engineered tumor models, which are NOTCH- dependent; (2) Efficacy in targeting a self renewing (“cancer stem cell”) population; (3) Potential cancer resistant mechanisms following NACK blockage; (4) Comprehensive pharmacokinetics and toxicology analyses in a future Phase II SBIR application. The clinical and market potential of a NACK-targeted NOTCH inhibitor for cancer treatment is enormous and fulfill a significant unmet need in patients.