TRAIL Upregulation by TIC10 Analogs

项目总结/摘要 TIC 10（ONC 201）是一类抗肿瘤剂和TRAIL基因的小分子诱导剂， 在我们的合作者Wafik El-Deiry博士实验室的高通量小分子文库筛选中鉴定， 宾夕法尼亚州立大学，并已被证明对几种难以治疗的疾病具有临床前疗效 包括未满足的临床需求的环境，如胶质母细胞瘤和三阴性乳腺癌。的 开发小分子TIC 10和类似物的动机是克服TIC 10的功效限制特性。 重组TRAIL和优化已经证明的TIC 10的优点（艾伦et al，2013）， 包括：（i）较长的半衰期，（ii）血清TRAIL的延长的升高，（iii）通过正常细胞的旁观者效应， TRAIL的产生，（iv）刺激TRAIL和死亡受体的表达，以及其他仅 通过小分子获得的，例如（V）稳定性，（VI）成本，（vii）口服活性，和（viii）穿过微生物系统的能力。 血脑屏障基于TIC 10的有希望的疗效和机制研究，已经开始努力 通过我们的合作开发，继续进行母体TIC 10化合物的临床前开发 Oncoceutics Inc.在人类身上进行概念验证试验。这里提出的项目旨在 鉴定更有效的TIC 10类似物，其保持TIC 10的功效和安全性特征，但是是新颖的， 适合商业开发。虽然TIC 10分子最初是在1971年合成的，但TIC 10是在1972年合成的。 该环系统的单个实例可用于我们的测定中的评价，除了TIC 10， 结构类别以前没有研究过生物活性。我们建议合成TIC 10类似物 确定更有效的先导化合物，并开发结构活性关系（SAR）数据， 促进活性的优化，同时产生新颖的、可申请专利的类似物。 这里提出的项目旨在利用我们的化学和生物学经验， 表征类似物并探索SAR（Aim 1），优化细胞和体内模型中的活性， 增强药物特性（Aim 2）。第一阶段申请的探索性工作还计划 产生专有变体和新的物质组成知识产权， 药物先导优化的途径，未来的临床试验和商业化治疗困难的 癌的总之，这些研究旨在增加我们对TRAIL的基本和翻译理解。 诱导小分子，并发现一个上级先导化合物，将推动这类新的 将这些化合物用于临床，为没有其他治疗选择的癌症患者提供治疗益处。

Project Summary/Abstract TIC10 (ONC201) is a first-in-class antitumor agent and small molecule inducer of the TRAIL gene which was identified in a high-throughput small molecule library screen in the lab of our collaborator, Dr. Wafik El-Deiry at Penn State University and has been shown to have preclinical efficacy in several difficult-to-treat disease settings that include unmet clinical needs such as glioblastoma and triple-negative breast cancer. The motivation for developing the small molecule TIC10 and analogs is to overcome efficacy-limiting properties of recombinant TRAIL and to optimize advantages TIC10 that have been demonstrated (Allen et al, 2013), including: (i) longer half-life, (ii) prolonged elevation of serum TRAIL, (iii) a bystander effect through normal cell TRAIL production, (iv) stimulation of TRAIL and death receptor expression, and other properties that are only obtained by a small molecule, such as (v) stability, (vi) cost, (vii) oral activity, and (viii) ability to cross the blood-brain barrier. Based on promising efficacy and mechanistic studies with TIC10, efforts have begun to pursue preclinical development of the parent TIC10 compound through our collaborating development company, Oncoceutics Inc. toward a proof-of-concept trial in humans. The project proposed here is intended to identify more potent analogs of TIC10 that maintain the efficacy and safety profile of TIC10 but are novel and suitable for commercial development. While the TIC10 molecule was originally synthesized in 1971, TIC10 was the single example of this ring system available for evaluation in our assays and except for TIC10, this structural class has not been previously studied for biological activity. We propose to synthesize TIC10 analogs to identify a more potent lead compound and to develop structure-activity relationship (SAR) data that would facilitate optimization of activity while generating novel, patentable analogs. The project proposed here is intended to leverage our chemistry and biology experience to synthesize and characterize analogs and to explore SAR (Aim1) and to optimize activity in cellular and in vivo models and to enhance pharmaceutical properties (Aim2). The exploratory work in this phase I application is also planned to generate proprietary variants and novel composition of matter intellectual property that would establish a pathway toward drug lead optimization, future clinical trials and commercialization for the treatment of difficult cancers. Together, these studies are aimed to increase our basic and translational understanding of TRAIL- inducing small molecules and to uncover a superior lead compound that would advance this novel class of compounds to the clinic to offer therapeutic benefit to cancer patients without other treatment options.