Chemical Biology Studies of Human Disease-Relevant Small Molecules

描述（由申请人提供）：本项目旨在阐明抗增殖天然产物OSW-1、schweinfurthin A、ritterazine B和cephalostatin 1（所谓的CRAMs）的细胞靶点和机制。由于这些小分子对培养的人类癌细胞系表现出令人兴奋的活性，并且在某些情况下，在小鼠异种移植癌症模型中表现出体内活性，因此揭示其分子机制可能会揭示用于治疗癌症的新蛋白质靶点。我们已经发现CRAMs结合OSBP（氧固醇结合蛋白）并干扰其在细胞中的活性。我们获得的进一步证据表明，ORP（OSBP相关蛋白）可能介导CRAMs的细胞毒性活性。在这项资助中，我们将1）确定哪些ORP介导CRAMs的细胞毒性活性，2）探索为什么CRAMs对癌细胞具有细胞毒性。我们预期这些研究将阐明CRAMs的作用模式，证明OSBP/ORP是癌细胞存活所需的非预期蛋白质，并揭示OSBP/ORP作为治疗癌症的新蛋白质靶点。此外，我们将公开CRAM是第一个有效和特异性干扰OSBP/ORP的小分子，从而能够研究其细胞功能。 公共卫生相关性：本项目将阐明抗增殖小分子的细胞靶点和机制，并将其应用于癌症治疗。在这些研究中获得的知识也可能揭示OSBP/ORP蛋白家族的新功能，可能应用于动脉粥样硬化和阿尔茨海默病。

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.