Molecular Inhibition of Apoptosis Inhibitors

细胞凋亡抑制剂的分子抑制

基本信息

批准号：
8235333
负责人：
JOHN C REED
金额：
$ 47.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8235333
关键词：
3&apos Untranslated Regions Accounting Apoptosis Apoptosis Inhibitor Apoptotic BH3 Domain Binding Cell Nucleus Cells Chemicals Chronic Lymphocytic Leukemia Clinic Clinical Code Cytoplasm Development Drug Combinations Failure Family Family member Genes Goals Human Human Genome In Vitro Inhibition of Apoptosis Instruction Leukemic Cell Longevity Messenger RNA MicroRNAs Modeling Molecular Mus NR4A1 gene New Agents Nuclear Nucleotides Orphan Pathogenesis Pharmaceutical Preparations Preclinical Testing Protein Family Proteins RNA Processing RNA-Induced Silencing Complex Research Resistance Ribonuclease III Ribonucleoproteins Site Structure Testing Transcript Transgenic Mice Untranslated RNA Western World analog chemotherapy effective therapy fascinate human DICER1 protein improved leukemia member mouse model neurotensin mimic 2 novel novel strategies preclinical study receptor binding small molecule

项目摘要

PROJECT SUMMARY (See instructions): PROJECT 2: Molecular Inhibition of Apoptosis Inhibitors B-cell chronic lymphocytic leukemia [B-CLL] arises primarily because of failures in apoptosis mechanisms. Aberrant over-expression of anti-apoptotic Bcl-2 family proteins contributes greatly to the long lifespan of CLL cells, and also thwarts attempts to eradicate these leukemic cells by chemotherapy. The human genome contains six genes encoding anti-apoptotic Bcl-2 family proteins (Bcl-2, BCI-XL, Mcl-1, Bfl-1, Bcl-W, Bcl-B), several of which are often highly expressed in CLLs. Expression of Mcl-1 or Bfl-1 accounts for resistance to chemical antagonists of Bcl-2, such as ABT263 analogs. Moreover, expression of these pro survival proteins increases in CLL cells thriving in microenvironmental niches. We hypothesize that redundancy caused by multiple anti-apoptotic Bcl-2 family members is a critical barrier to effective treatment of CLL. We propose to test this hypothesis through 3 complementary approaches. First. ABT263 and other small molecule Bcl-2 antagonists currently in clinical development bind a regulatory site on Bcl-2, mimicking endogenous antagonists that contain the BH3 domain. We have generated novel BH3 mimicking compounds with broad-spectrum inhibitory activity against all anti-apoptotic Bcl-2 family proteins. These compounds will be tested for preclinical activity against primary human CLL cells in culture and against murine CLL cells in transgenic mouse models. Second, we have identified a non-BH3 regulator of Bcl-2 in the Nur77/TR3 protein, an orphan nuclear receptor that binds to Bcl-2, Bfl-1, and Bcl-B, converting these proteins from antito pro-apoptotic. Using Nur77/TR3, we have discovered a novel non-BH3 regulatory site on Bcl-2 family proteins that will be targeted with small molecules as an alternative approach to Bcl-2 antagonism. Third. expression of many anti-apoptotic Bcl-2 family proteins (including Mel-1, BCI-XL, and Bfl-1) is upregulated when CLL cells are influenced by microenvironment. Hence, agents from Aims 1 and 2 will be evaluated for activity against CLL cells using in vitro culture models of microenvironment interactions. Altogether, our goal is to extend preclinical studies of novel Bcl-2 family antagonists towards the ultimate goal of bringing these concepts and new agents into the clinic via the CLL Research Consortium (CRC).

项目摘要（请参阅说明）：项目2：分子抑制细胞凋亡抑制剂 B细胞慢性淋巴细胞性白血病[B-CLL]主要是由于细胞凋亡机制失败。抗凋亡Bcl-2家族蛋白的异常过表达对长期寿命有很大贡献 CLL细胞，也试图通过化学疗法消除这些白血病细胞。人类基因组包含六个编码抗凋亡Bcl-2家族蛋白（BCL-2，BCI-XL，MCL-1，BFL-1，BCL-W，BCL-B）的基因，其中几种通常在CLL中高度表达。 MCL-1或BFL-1的表达对Bcl-2的化学拮抗剂的抗性，例如ABT263类似物。而且，这些专业的表达生存蛋白在微环境壁ches中蓬勃发展的CLL细胞中增加。我们假设这一点由多种抗凋亡BCL-2家族成员引起的冗余是有效治疗CLL的关键障碍。我们建议通过3种互补方法检验这一假设。第一的。 ABT263和其他临床发育中的其他小分子Bcl-2拮抗剂结合了Bcl-2上的调节位点，模仿包含BH3结构域的内源性拮抗剂。我们已经产生了具有广谱抑制活性的新型BH3化合物对所有抗凋亡Bcl-2家族蛋白。这些化合物将在培养物中对原代人CLL细胞的临床前活性和转基因小鼠模型中的鼠CLL细胞进行测试。其次，我们在NUR77/TR3蛋白（一种与Bcl-2，BFL-1和BCl-B结合的孤儿核受体中鉴定了BCl-2的非BH3调节剂，从抗抗蛋白pro-apoptotic中转化了这些蛋白质。使用NUR77/TR3，我们在Bcl-2家族蛋白上发现了一种新型的非BH3调节位点，该蛋白将以小分子为目标，作为Bcl-2拮抗作用的替代方法。第三。当CLL细胞受微环境影响时，许多抗凋亡BCL-2家族蛋白（包括MEL-1，BCI-XL和BFL-1）的表达被上调。因此，将使用微环境相互作用的体外培养模型评估目标1和2的药物对CLL细胞的活性。总的来说，我们的目标是将新型BCL-2家族拮抗剂的临床前研究扩展到通过CLL研究联盟（CRC）将这些概念和新代理带入诊所的最终目标。