Structure-based anti-cancer drug development

基于结构的抗癌药物开发

• 批准号: 8112487
• 负责人: Xingming Deng
• 金额: $ 31万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-16 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8112487
• 关键词: Affinity; Animal Model; Antineoplastic Agents; Apoptosis; Apoptotic; BH4 Domain; Binding; Biological Assay; Cancer Etiology; Cell Death; Cells; Data; Databases; Development; Docking; Epithelial Cells; Excision; Family; Growth; Human; Lead; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Molecular; Names; National Cancer Institute; Non-Small-Cell Lung Carcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Resistance; Screening procedure; Sirolimus; Site; Structure; Testing; Tumor Tissue; Xenograft procedure; base; cancer cell; cancer therapy; chemotherapy; computerized; design; drug development; human FRAP1 protein; improved; in vivo; inhibitor/antagonist; lung small cell carcinoma; mTOR Inhibitor; mTOR inhibition; member; mortality; neoplastic cell; novel; novel strategies; outcome forecast; overexpression; programs; public health relevance; small molecule; therapeutic target; tumor growth

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer-related mortality and most patients with lung cancer have poor prognosis due to chemoresistance. Development of more effective, new drugs that act through basic molecular mechanisms, including apoptosis, to overcome chemoresistance is critical to improve the prognosis of patients with lung cancer. Bcl2, a major antiapoptotic molecule, is extensively expressed in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cells. One major factor implicated in the resistance to chemotherapy is the overexpression of Bcl2, suggesting that Bcl2 should be an attractive therapeutic target in human lung cancer. The BH4 domain of Bcl2, which encompasses an amphipathic a1-helix, has been demonstrated to be a required domain for Bcl2's antiapoptotic function. Therefore, we chose the BH4 domain as a docking site for screening of small molecules that may inactivate Bcl2 using the computerized DOCK program and a database from the National Cancer Institute (NCI). Two hundred of the compounds determined to have the highest affinity were obtained from the NCI and tested for their effects on cell death. Four of the two hundred compounds have been found to potently induce apoptosis of various human lung cancer cells. We named these compounds as small molecule Bcl2 inhibitors (i.e. SMBI-1~4). Intriguingly, SMBI-1~4 represent significantly less apoptotic effect on normal small airway epithelial cells as compared to lung cancer cells, indicating a selectivity of these compounds for tumor cells. The lead SMBI potently represses tumor growth in association with increased apoptosis in tumor tissues in NSCLC animal models. These preliminary findings suggest that SMBI(s) may have great potential to be developed as a new class of anti-lung cancer drugs. Modulation of the mTOR pathway is being clinically developed as an advanced strategy for lung cancer treatment. However, expression of Bcl2 is associated with resistance of lung cancer cells to mTOR inhibitor(s). Thus, an effective way to enhance the sensitivity of lung cancer cells to mTOR inhibition is to combine a mTOR inhibitor with a Bcl2 inhibitor (i.e. SMBI). Our preliminary data reveal that treatment of lung cancer cells with a combination of SMBI and rapamycin not only synergistically induces apoptosis but also augments growth inhibition, suggesting that the combined mTOR and Bcl2 inhibition may additively suppress lung tumor growth, leading to sustained regression in vivo. To critically test these hypotheses, we have identified two specific aims: (1) To determine the mechanism(s) by which SMBI(s) induces apoptosis in human lung cancer cells; (2) To determine whether SMBI(s) represses tumor growth in both SCLC and NSCLC xenografts. Studies will evaluate whether co-targeting Bcl2 and mTOR by a combination of SMBI and a mTOR inhibitor synergistically improves the anti-lung cancer efficacy in vivo. From the results, it is expected that a new class of anti-cancer drugs and a more effective approach for cancer treatment will be developed by co-targeting Bcl2 and mTOR. PUBLIC HEALTH RELEVANCE: Project Narrative Most patients with lung cancer have a poor prognosis due to chemoresistance. Development of more effective new drugs that act through basic molecular mechanisms to overcome chemoresistance is critical to improve the prognosis of patients with lung cancer. Studies in this proposal are designed to develop small molecules as novel anti-lung cancer drugs that inhibit the antiapoptotic function of Bcl2 in lung cancer cells.

描述（申请人提供）：肺癌是癌症相关死亡的主要原因，大多数肺癌患者由于化疗耐药而预后较差。开发更有效的新药，通过包括细胞凋亡在内的基本分子机制来克服化疗耐药，对于改善肺癌患者的预后至关重要。Bcl2是一种主要的抗凋亡分子，在小细胞肺癌（SCLC）和非小细胞肺癌（NSCLC）细胞中广泛表达。化疗耐药的一个主要因素是Bcl2的过表达，这表明Bcl2应该是人类肺癌的一个有吸引力的治疗靶点。Bcl2的BH4结构域包含一个两亲a1-螺旋，已被证明是Bcl2抗凋亡功能所必需的结构域。因此，我们选择BH4结构域作为对接位点，使用计算机DOCK程序和国家癌症研究所（NCI）的数据库筛选可能使Bcl2失活的小分子。从NCI中获得了200种被确定具有最高亲和力的化合物，并测试了它们对细胞死亡的影响。在这200种化合物中，有4种已被发现能有效地诱导各种人类肺癌细胞的凋亡。我们将这些化合物命名为小分子Bcl2抑制剂（即SMBI-1~4）。有趣的是，与肺癌细胞相比，SMBI-1~4对正常小气道上皮细胞的凋亡作用明显较小，表明这些化合物对肿瘤细胞具有选择性。在非小细胞肺癌动物模型中，SMBI先导物能有效抑制肿瘤生长并增加肿瘤组织的凋亡。这些初步研究结果表明，SMBI(s)作为一类新的抗肺癌药物可能具有很大的开发潜力。作为肺癌治疗的一种先进策略，mTOR通路的调节正在临床开发中。然而，Bcl2的表达与肺癌细胞对mTOR抑制剂的耐药性有关。因此，将mTOR抑制剂与Bcl2抑制剂（即SMBI）联合使用是提高肺癌细胞对mTOR抑制敏感性的有效途径。我们的初步数据显示，SMBI和雷帕霉素联合治疗肺癌细胞不仅可以协同诱导细胞凋亡，还可以增强生长抑制，这表明mTOR和Bcl2联合抑制可能会累加抑制肺肿瘤的生长，导致体内持续的消退。为了严格检验这些假设，我们确定了两个具体目标：(1)确定SMBI诱导人肺癌细胞凋亡的机制；(2)确定SMBI是否抑制SCLC和NSCLC异种移植物的肿瘤生长。研究将评估SMBI和mTOR抑制剂联合靶向Bcl2和mTOR是否能协同提高体内抗肺癌疗效。从研究结果来看，通过Bcl2和mTOR的共同靶向，有望开发出一类新的抗癌药物和更有效的癌症治疗方法。