TRAIL Upregulation by TIC10 Analogs

TIC10 类似物对 TRAIL 的上调

• 批准号: 8643115
• 负责人: WAFIK S. EL-DEIRY
• 金额: $ 22.5万
• 依托单位: PROVID PHARMACEUTICALS, INC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8643115
• 关键词: Animal Model; Biological; Biological Assay; Biology; Blood; Blood - brain barrier anatomy; Brain; Bystander Effect; Cancer Patient; Cell model; Cessation of life; Chemistry; Clinic; Clinical; Clinical Treatment; Clinical Trials; Data; Development; Disease; Dose; Ensure; Evaluation; Future; Genes; Glioblastoma; Half-Life; Human; Human Cell Line; Intellectual Property; Lead; Malignant Neoplasms; Motivation; Mus; Nitrogen; Normal Cell; Nuclear Translocation; Oral; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Positioning Attribute; Pre-Clinical Model; Production; Property; Recombinants; Safety; Serum; Signal Transduction; Solubility; Structure; Structure-Activity Relationship; System; TNFSF10 gene; Therapeutic; Titrations; Translating; Universities; Up-Regulation; Variant; Work; Xenograft procedure; analog; antitumor agent; base; cancer therapy; commercialization; cost; cytotoxicity; experience; gene induction; improved; in vivo Model; innovation; lead series; mouse model; novel; novel therapeutic intervention; pre-clinical; preclinical efficacy; protein function; public health relevance; receptor expression; small molecule; small molecule libraries; subcutaneous; success; triple-negative invasive breast carcinoma; tumor

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.

项目摘要/摘要 TIC10（ONC201）是一流的抗肿瘤剂和小分子诱导剂，是该基因的小分子诱导剂 在我们的合作者Wafik El-Deiry博士的实验室中的高通量小分子库屏幕中确定 宾夕法尼亚州立大学，已被证明在几种难以治疗的疾病中具有临床前疗效 包括未满足的临床需求的设置，例如胶质母细胞瘤和三阴性乳腺癌。这 开发小分子TIC10和类似物的动机是克服效率限制特性 重组步道并优化已证明的优势TIC10（Allen等，2013）， 包括：（i）更长的半衰期，（ii）血清步道的长时间升高，（iii）通过正常细胞的旁观者效应 步道生产，（iv）刺激跟踪和死亡受体表达，而其他仅是其他特性 通过一个小分子获得，例如（v）稳定性，（vi）成本，（vii）口服活动，以及（viii）越过的能力 血脑屏障。基于有前途的功效和TIC10的机理研究，努力已经开始 通过我们的协作开发来追求父tic10复合的临床前开发 公司Oncoutics Inc.进行人类的概念验证审判。这里提出的项目旨在 确定TIC10的更有效的类似物，以保持TIC10的功效和安全性，但是新颖的，并且 适合商业发展。虽然TIC10分子最初是在1971年合成的，但TIC10为 此环系统的一个示例可在我们的测定中进行评估，除TIC10外， 以前尚未研究结构类别的生物活性。我们建议合成TIC10类似物 确定更有效的铅化合物并建立结构活性关系（SAR）数据 在产生新颖，可申请的类似物的同时，促进活动的优化。 这里提出的项目旨在利用我们的化学和生物学经验来综合和 表征类似物并探索SAR（AIM1），并优化细胞和体内模型中的活动以及 增强药物特性（AIM2）。该阶段I应用程序还计划进行探索性工作 产生专有变体和物质知识产权的新颖组成，这些物质将建立一个 药物铅优化，未来临床试验和商业化的途径，以治疗困难 癌症。这些研究共同旨在提高我们对步道的基本和翻译的理解 - 诱导小分子并揭示将推进这一新类型的优质铅化合物 诊所的化合物可为没有其他治疗选择的癌症患者提供治疗益处。