Chemical Biology Studies of Human Disease-Relevant Small Molecules

人类疾病相关小分子的化学生物学研究

• 批准号: 7985853
• 负责人: Matthew D. Shair
• 金额: $ 48.95万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7985853
• 关键词: Alzheimer' s Disease; Atherosclerosis; Binding; Biological Factors; Biology; Cancer Model; Cancer cell line; Cell Survival; Cell physiology; Cells; Cephalostatin; Chemicals; Exhibits; Grant; Human; Knowledge; Malignant Neoplasms; Mediating; Molecular; Mus; Protein Family; Proteins; Xenograft procedure; analog; cancer cell; cancer therapy; cellular targeting; cytotoxic; cytotoxicity; human disease; in vivo; oxysterol binding protein; public health relevance; schweinfurthin A; small molecule

DESCRIPTION (provided by applicant): This project is to elucidate the cellular target and mechanism of the antiproliferative natural products OSW-1, schweinfurthin A, ritterazine B, and cephalostatin 1 (so-called CRAMs). Since these small molecules have shown exciting activity against cultured human cancer cells lines, and in some cases, in vivo activity in mouse xenograft cancer models, uncovering their molecular mechanisms may reveal new protein targets for treating cancer. We have discovered that CRAMs bind OSBP (oxysterol binding protein) and perturb its activity in cells. Further evidence we have obtained suggests that ORPs (OSBP-related proteins) are likely mediating the cytotoxic activity of CRAMs. In this grant, we will 1) Determine which ORPs are mediating the cytotoxic activity of CRAMs and 2) Explore Why CRAMs are Cytotoxic to Cancer Cells. We anticipate that these studies will clarify the mode of action of CRAMs, demonstrate that OSBP/ORPs are unanticipated proteins required for cancer cell survival and reveal OSBP/ORPs as new protein targets for the treatment of cancer. In addition, we will disclose that CRAMs are the first small molecules that potently and specifically perturb OSBP/ORPs, enabling studies of their cellular functions. PUBLIC HEALTH RELEVANCE: This project will elucidate the cellular target and mechanisms of antiproliferative small molecules with application to cancer treatment. Knowledge gained in these studies may also reveal new functions of the OSBP/ORP family of proteins with possible applications in atherosclerosis and Alzheimer's disease.

描述（由申请人提供）：该项目是为了阐明抗粉状天然产物OSW-1，schweinfurthin A，Ritterazine B和Cephalostatin 1（所谓的CRAMS）的细胞靶和机制。由于这些小分子已经显示出针对培养的人类癌细胞系的令人兴奋的活性，在某些情况下，在小鼠异种移植癌模型中的体内活性，发现它们的分子机制可能会揭示出新的治疗癌症的蛋白质靶标。我们发现CRAMS结合OSBP（氧蛋白酶结合蛋白）并扰动其在细胞中的活性。我们获得的进一步证据表明，ORP（与OSBP相关的蛋白质）可能正在介导CRAM的细胞毒性活性。在这笔赠款中，我们将1）确定哪些ORP介导了CRAMS的细胞毒性活性，并探讨为什么CRAM对癌细胞具有细胞毒性。我们预计这些研究将阐明crams的作用方式，证明OSBP/ORP是癌细胞存活所需的意外蛋白质，并揭示OSBP/ORP作为治疗癌症治疗的新蛋白质靶标。此外，我们将透露cram是有力，特别是扰动OSBP/ORP的第一个小分子，从而可以研究其细胞功能。 公共卫生相关性：该项目将阐明抗增殖性小分子的细胞靶标和机制，并应用于癌症治疗。在这些研究中获得的知识也可能揭示了OSBP/ORP蛋白质家族在动脉粥样硬化和阿尔茨海默氏病中可能应用的新功能。