Molecular Inhibition of Apoptosis Inhibitors

细胞凋亡抑制剂的分子抑制

• 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
• 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' 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

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).

项目总结（见说明）： 项目2：细胞凋亡抑制剂的分子抑制 B细胞慢性淋巴细胞白血病[B-CLL]的出现主要是因为细胞凋亡机制的失败。 抗凋亡Bcl-2家族蛋白的异常过表达极大地促进了细胞的长寿命。 CLL细胞，并且也阻碍了通过化疗根除这些白血病细胞的尝试。人类 基因组含有编码抗凋亡Bcl-2家族蛋白（Bcl-2、BCI-XL、Mcl-1、Bfl-1、Bcl-W、Bcl-B）的六种基因，其中几种通常在CLL中高度表达。Mcl-1或Bfl-1的表达解释了 对Bcl-2的化学拮抗剂如ABT 263类似物的抗性。此外，表达这些亲 生存蛋白在CLL细胞中增加，在微环境小生境中茁壮成长。我们假设 由多个抗凋亡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种互补的方法来验证这一假设。先目前在临床开发中的ABT 263和其他小分子Bcl-2拮抗剂结合Bcl-2上的调节位点，模拟含有BH 3结构域的内源性拮抗剂。我们已经产生了新的BH 3模拟化合物，对所有抗凋亡Bcl-2家族蛋白具有广谱抑制活性。将测试这些化合物针对培养物中的原代人CLL细胞和转基因小鼠模型中的鼠CLL细胞的临床前活性。第二，我们已经在Nur 77/TR 3蛋白中鉴定了Bcl-2的非BH 3调节剂，Nur 77/TR 3蛋白是一种孤儿核受体，其结合Bcl-2、Bfl-1和Bcl-B，将这些蛋白从抗凋亡蛋白转化为促凋亡蛋白。使用Nur 77/TR 3，我们发现了Bcl-2家族蛋白上的一个新的非BH 3调节位点，该位点将被小分子靶向作为Bcl-2拮抗作用的替代方法。三分之当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）的表达上调。因此，将使用微环境相互作用的体外培养模型评价目的1和2的药物对CLL细胞的活性。总而言之，我们的目标是通过CLL研究联盟（CRC）将这些概念和新药物带入临床的最终目标，扩展新型Bcl-2家族拮抗剂的临床前研究。