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

摘要 异常激活的Noch信号在一系列癌症类型的肿瘤发生中起作用，包括 食管腺癌(EAC)，其发病率在过去40年中增加了两倍，总体状况不佳 五年存活期。Notch Activation Complex Kinase(NACK)是Notch信号的共同激活剂，并且是 通常在缺口依赖型癌症中过度表达。NACK基因缺失是根除NACK的有效方法 临床前模型中的缺口依赖性EACS，表明NACK是一个有前途的治疗靶点 缺口依赖型癌症。通过与迈阿密大学的许可协议，我们已经获得了 独家开发针对NACK结构域(INACKs)的小分子，以治疗 依赖缺口/NACK的癌症。到目前为止，我们已经开发了几种iNACK，可以防止NACK被 募集到Noch转录复合体，抑制Noch途径的激活，并抑制生长 在细胞培养和小鼠体内检测依赖Noch/NACK的EAC。此外，我们还表明，我们早期的领先产品iNACK 不会引起胃肠道轨迹(GI)毒性，而GI毒性通常与伽马引起的切迹堵塞有关 分泌酶抑制剂。因此，我们假设通过抑制NACK来阻断缺口信号将 在缺口依赖型癌症中安全有效。 我们建议的目标是开发下一代iNACK，它们更强大、更具体、更具备 更好的类药物特性。我们提出两个具体目标： A1.通过以下结构开发具有更高效力、选择性和药代动力学特性的iNACK- 活度关系(SAR)研究。 A2.通过ADMET评价SSTK-0388等iNACK的类药物特性和体内疗效 药代动力学(PK)和小鼠异种移植研究。 这些目标将建立多达两种领先的iNACK化合物以供进一步开发，包括：(1)在 更多的人类患者来源的异种移植和基因工程肿瘤模型，这些都是缺口- 依赖；(2)靶向自我更新(“癌症干细胞”)群体的有效性；(3)潜在癌症 NACK阻断后的耐药机制；(4)综合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靶向切迹的临床和市场潜力 用于癌症治疗的抑制剂是巨大的，满足了患者尚未得到满足的重大需求。

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.