SMIP004/SMIP004-7系列线粒体抑制剂作用机制及应用于去势抵抗性前列腺癌治疗的潜力研究

Castration-resistant prostate cancer (CRPC) is a major public health problem claiming ~26,000 lives per year in China alone. Standard-of-care therapy for advanced prostate cancer is androgen deprivation therapy combined with chemotherapy. On the basis that CRPC continues to depend on androgen receptor function, new anti-androgens and androgen synthesis blockers were introduced to the clinic with substantial therapeutic success. However, rapid development of resistance indicates a strong unmet need for alternative therapies. The PI’s lab has previously discovered compound SMIP004-7, a novel inducer of apoptosis selectively in CRPC cells. Chemogenomic and proteomic profiling revealed that the compound induces a pro-apoptotic pathway, which initiates with inhibition of mitochondrial respiration complex I (NADH dehydrogenase), leading to oxidative stress. Oxidative stress activates pro-apoptotic signaling through the unfolded protein response pathway. SMIP004-7 potently inhibited the growth of CRPC xenografts in mice with no obvious toxicity. The recent recognition that therapy resistance coincides with upregulation of mitochondrial respiration in a variety of tumor types led to the proposition that mitochondrial inhibition is a promising novel approach to target a specific bioenergetic liability of CRPCs failing chemo-hormonal therapy. The main objective of this exploratory research is to assess the potential of chemical compound SMIP004-7 as a novel therapy for CRPC. By identifying the molecular target of SMIP004-7 and biomarkers to select patients that will likely benefit from SMIP004-7 as well as obtaining SAR information for compound optimization, providing an initial toxicology profile and establishing further in vivo efficacy, accomplishing the goals of this project will set the stage for further preclinical development of a SMIP004-7-based treatment of drug-resistant prostate cancer.

去势抵抗性前列腺癌（CRPC）在中国每年造成约2.6万男性死亡，已经成为严重的社会问题。目前对于CRPC的标准疗法是荷尔蒙去除疗法结合化疗。然而荷尔蒙疗法快速产生的耐药性使得急需开发另外的治疗药物。申请人实验室前期发现的化合物SMIP004-7可选择性诱导CRPC细胞凋亡。基因组学和蛋白组学分析发现该化合物通过抑制线粒体呼吸链复合物I导致氧化应激压力，激活非折叠蛋白效应，启动细胞凋亡。动物实验发现SMIP004-7有效的抑制CRPC生长，无明显毒性反应。本项目的主要目的是评价新型化合物SMIP004-7治疗CRPC的潜力。通过确认SMIP004-7的分子靶点和敏感性标记物、明确该系列化合物构效关系从而优化化合物、获得毒理学数据并确认其体内抗肿瘤活性，本项目的成果将对以SMIP004-7为基础的耐药性前列腺癌药物开发和理解线粒体抑制剂的抗癌作用机理提供重要的指导。

SMIP004-7是具有选择性的线粒体小分子抑制剂，目前其分子靶点尚不明确。本项目研究发现SMIP004-7通过靶向线粒体复合物I，从而抑制肿瘤细胞的干性，具有克制肿瘤耐药的潜力。与大多数线粒体抑制靶向醌结合位点不同，SMIP004-7非竞争性结合线粒体复合体催化位点NDUFS2的氮端，从而使复合体解体而抑制线粒体活性。通过抑制NDUFS2，SMIP004-7及其衍生物体内抑制三阴性乳腺癌异种移植物，其机制与激发免疫监视功能有关。因此，SMIP004-7定义了一类新型线粒体抑制剂，以非竞争性抑制线粒体复合体I的机制调控肿瘤微环境并靶向抑制肿瘤细胞的线粒体呼吸功能。本项目的研究成果将为新型线粒体抑制剂类抗癌药物的开发提供宝贵的理论指导和提示。

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