The Development of Novel Inhibitors of BCL2 Gene Expression as Anticancer Therape

开发新型 BCL2 基因表达抑制剂作为抗癌疗法

基本信息

批准号：
8642980
负责人：
LAURENCE H. HURLEY
金额：
$ 22.5万
依托单位：
TETRAGENE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-20 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8642980
关键词：
Acute Anti-Inflammatory Agents Anti-inflammatory Antineoplastic Agents Apoptosis Apoptotic Area Arizona BCL2 gene Back Binding Biochemical Biological Assay Biological Factors Cancer cell line Caring Cell Culture Techniques Cell Survival Cells Chemistry Chronic Clinical Clinical Trials DNA DNA Structure Development Drug Kinetics Evaluation Family member G-Quartets Gene Expression Gene Targeting Genes Genetic Transcription Goals In Vitro Isoquinolines Lead Ligation Lymphocyte Lymphoma Maintenance Malignant Neoplasms Malignant lymphoid neoplasm Maximum Tolerated Dose Measurable Mus Nuclear Receptors Pharmaceutical Preparations Phase I Clinical Trials Plastics Play Promoter Regions Protein Family Proteins Qualifying Rattus Reaction Regulation Regulator Genes Regulatory Element Resistance Role Safety Series Side Signal Transduction Staging Structure Surveys Suspension substance Suspensions Synthesis Chemistry Testing Tumor Lysis Syndrome Uncertainty Universities Work Xenograft Model Xenograft procedure analog base cancer cell chemotherapy cytotoxic design drug discovery expectation high throughput screening in vivo inhibitor/antagonist innovation lead series member mimetics neoplastic cell novel overexpression preclinical study programs promoter public health relevance screening small molecule tumor tumorigenesis

项目摘要

Project Summary Evasion of apoptosis is a hallmark of cancer and is associated with oncogenesis, tumor maintenance, and resistance to conventional chemotherapy. BCL-2 was the first identified anti-apoptotic factor and is a member of the BCL-2 family of proteins that cooperate in the regulation of programmed cell death. BCL-2 plays a dominant role in the survival of multiple lymphoid malignancies and has consequently become an active target for drug discovery programs seeking to reactivate dormant apoptotic signaling in cancer cells or enhance the activity of cytotoxic anticancer drugs. The only small-molecule-based approach has been to target the BH3 binding domain of Bcl-2, thereby blocking interaction with other pro-apoptotic Bcl-2 family members. However, the recent suspension of the BH3 mimetic ABT-119 from clinical trials, due to the occurrence of tumor lysis syndrome, has cast some doubt over the potential safety of the BH3 mimetic approach and increased the need for alternative strategies to target BCL-2. In common with many other genes that cooperate in the development and maintenance of cancer, BCL-2 contains a highly plastic, GC-rich transcriptional regulatory element in its promoter region. Pioneering work at the University of Arizona has shown that this regulatory element is capable of forming DNA secondary structures called G-quadruplex DNA (G-rich strand) and i-motif DNA (C-rich strand) and that these DNA secondary structures regulate transcription. A high-throughput screening assay designed to identify small molecules capable of stabilizing/destabilizing the BCL-2 i-motif sequence produced a small molecule from the steroidal chemotype (IMC-76). Subsequent studies have demonstrated that IMC-76 decreases BCL-2 expression in cell culture and in mouse xenograft tumor cells. Importantly, IMC-76 significantly potentiates apoptosis induced by conventional chemotherapy drugs in cell culture and demonstrates considerable synergy when combined with chemotherapy drugs in mouse cancer xenograft models. The ultimate goal of this proposal is to advance suitably optimized analogs of IMC-76 into IND-enabling studies and eventual phase 1 clinical trials. We propose a limited round of synthetic chemistry for the purpose of optimizing potency for lowering BCL-2 expression in cells and synergy with cytotoxic anticancer drugs in cell culture. Furthermore, this optimization strategy will allow us to explore potential off-target effects associated with the steroidal chemotype by screening analogs in biochemical nuclear receptor assays. Qualified lead molecules will be subjected to pharmacokinetic analysis in rats, both chronic and acute tolerability studies in mice, and efficacy studies in combination with standard-of-care chemotherapy drugs in lymphoma mouse xenograft models. Collectively these studies will enable us to select an optimized lead candidate for advancement into formal preclinical studies.

项目概要逃避细胞凋亡是癌症的一个标志，与肿瘤发生、肿瘤维持和癌症相关。对常规化疗产生耐药性。 BCL-2是第一个被鉴定的抗凋亡因子，是成员 BCL-2 蛋白家族的成员，协同调节程序性细胞死亡。 BCL-2 发挥着在多种淋巴恶性肿瘤的生存中起主导作用，因此已成为一个活跃的目标用于寻求重新激活癌细胞中休眠的细胞凋亡信号或增强癌细胞的药物发现计划细胞毒性抗癌药物的活性。唯一基于小分子的方法是针对 BH3 Bcl-2 的结合域，从而阻断与其他促凋亡 Bcl-2 家族成员的相互作用。然而，由于发生肿瘤溶解，BH3 模拟物 ABT-119 最近暂停临床试验综合症，使人们对 BH3 模拟方法的潜在安全性产生了一些怀疑，并增加了对 BH3 模拟方法的需求了解针对 BCL-2 的替代策略。与许多其他参与癌症发生和维持的基因一样，BCL-2 在其启动子区域含有高度可塑性、富含 GC 的转录调控元件。开创性工作于亚利桑那大学已经证明这种调控元件能够形成 DNA 次级称为 G-四链体 DNA（富含 G 链）和 i-基序 DNA（富含 C 链）的结构，并且这些 DNA 二级结构调节转录。旨在识别小分子的高通量筛选测定能够稳定/不稳定 BCL-2 i-motif 序列的分子产生了一个小分子类固醇化学型（IMC-76）。随后的研究表明 IMC-76 降低 BCL-2 在细胞培养物和小鼠异种移植肿瘤细胞中表达。重要的是，IMC-76 显着增强传统化疗药物在细胞培养物中诱导细胞凋亡，并表现出相当大的协同作用在小鼠癌症异种移植模型中与化疗药物联合使用时。该提案的最终目标是将经过适当优化的 IMC-76 类似物推进 IND 研究以及最终的一期临床试验。我们提议进行一轮有限的合成化学，目的是优化降低细胞中 BCL-2 表达的效力以及与细胞中细胞毒性抗癌药物的协同作用文化。此外，这种优化策略将使我们能够探索相关的潜在脱靶效应通过在生化核受体测定中筛选类似物来确定类固醇化学型。合格铅分子将在大鼠中进行药代动力学分析，以及慢性和急性耐受性研究小鼠，以及与标准护理化疗药物联合治疗淋巴瘤小鼠的疗效研究异种移植模型。总的来说，这些研究将使我们能够选择一个优化的主要候选药物进入正式的临床前研究。