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

摘要 异常激活的NOTCH信号传导有助于一系列癌症类型的肿瘤发生，包括 食管腺癌（EAC），其发病率在过去40年中增加了两倍， 五年生存率。Notch激活复合物激酶（NACK）是NOTCH信号传导的共激活剂，并且是 通常在NOTCH依赖性癌症中过表达。NACK的基因消除有效地消除了 在临床前模型中，N 0 TCH依赖性EAC是一种有希望的治疗靶点，这表明NACK是一种有希望的治疗靶点。 NOTCH依赖性癌症。通过与迈阿密大学的许可协议，我们获得了 开发靶向NACK激酶结构域（iNACK）的小分子的独家权利，以治疗 NOTCH/NACK依赖性癌症。到目前为止，我们已经开发了几种iNACK， 募集到NOTCH转录复合物，抑制NOTCH途径激活，并抑制细胞生长。 NOTCH/NACK依赖性EAC在细胞培养物和小鼠中的表达。此外，我们表明，我们的早期领先iNACK 不会引起胃肠道（GI）毒性，GI毒性通常与伽马辐照导致的NOTCH阻断有关 分泌酶抑制剂。因此，我们假设，通过抑制NACK阻断NOTCH信号传导将 安全有效地治疗NOTCH依赖性癌症。 我们建议的目标是开发下一代iNACK，更有效，更具体， 更好的药物性质。我们提出两个具体目标： A1.通过结构化开发具有改进的效力、选择性和药代动力学性质的iNACK- 活性关系（SAR）研究。 A2.通过ADMET评估SSTK-0388和其他iNACK的类药物性质和体内疗效， 药代动力学（PK）和小鼠异种移植物研究。 这些目标将建立多达两种用于进一步开发的先导iNACK化合物，包括： 更多的人类患者来源的异种移植物和基因工程肿瘤模型，这是NOTCH- 依赖性;（2）靶向自我更新（“癌症干细胞”）群体的功效;（3）潜在的癌症干细胞 NACK阻断后的耐药机制;（4）全面的药代动力学和毒理学 在未来的第二阶段SBIR应用中进行分析。NACK靶向NOTCH的临床和市场潜力 用于癌症治疗抑制剂是巨大的且满足了患者中显著未满足的需求。

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.