Inhibition of interleukin-6 production for the treatment of multiple myeloma

描述(申请人提供)：多发性骨髓瘤(MM)是一种分化的B细胞(浆细胞)的恶性疾病，目前仍无法治愈。MM细胞的生长和化疗耐药是由骨髓微环境通过持续表达和分泌趋化因子和细胞因子来支持的。骨髓瘤生长因子中最具特征性的是白介素6(IL-6)，它存在于MM患者的高血清水平，与MM的发病机制直接相关。因此，IL-6的产生被认为是抑制MM细胞生长和化疗耐药的治疗靶点。该提案的目标是产生有效的IL-6产生抑制剂，用于作为单一药物或现有疗法的添加剂，以提高多发性骨髓瘤治疗的整体治疗结果。我们实验室最近报道了一类小分子支架，它们是产生IL-6的有效抑制剂。这种先导化合物能够通过一种在文献中描述的其他抑制剂中独一无二的机制，在纳摩尔浓度下抑制人体血液中IL-6的产生。鉴于IL-6在多发性骨髓瘤发病机制中的核心作用，本建议着重于阐明这类抑制剂作为单一药物和辅助药物治疗多发性骨髓瘤的作用模式和优化。这项建议的目标是发现抑制IL-6的作用模式，通过在多发性骨髓瘤细胞中使用单一的辅助治疗来建立疗效，并设计和执行对映选择性合成以改善获得这些有效的IL-6抑制剂的途径。 公共卫生相关性：多发性骨髓瘤(MM)仍然无法治愈，由于IL-6介导的生长和生存途径的激活，MM细胞对传统化疗药物具有固有的耐药性。我们发现了一种有效的IL-6抑制剂，能够降低刺激的人血中IL-6的水平，并杀死MM细胞。这个项目的重点是确定这些药物的作用模式，并在模拟骨髓微环境的条件下在一系列MM细胞中建立疗效。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a malignant disorder of differentiated B-cells (plasma cells) and remains incurable. The growth and chemotherapeutic resistance of the MM cells is supported by the bone marrow microenvironment (BMM) through the continuous expression and secretion of chemokines and cytokines. The best-characterized myeloma growth factor is interleukin 6 (IL-6), which is found at high serum levels in MM patients, and has been directly related to the pathogenesis of MM. Consequently, IL-6 production has been identified as a therapeutic target to inhibit MM cell growth and resistance to chemotherapeutics. The goal of the proposal is to generate potent inhibitors of IL-6 production for the use as single agents, or as additives to current therapeutics, to enhance the overall therapeutic outcome of multiple myeloma treatment. Our lab has recently reported a class of small molecular weight scaffolds as potent inhibitors of IL-6 production. The lead compound was capable of inhibiting IL-6 production in human blood at nanomolar concentrations via a mechanism that may be unique among other inhibitors described in the literature. Given the central role of IL-6 in the pathogenesis of multiple myeloma, this proposal is focused on the elucidation of the mode of action and optimization of this class of inhibitors as single agents and adjuvant agents for the treatment of multiple myeloma. The goals of this proposal are to discover the mode of action for IL-6 inhibition, establishing efficacy by using single and adjuvant treatment in multiple myeloma cells and design and execute an enantioselective synthesis to improve access to these potent IL-6 inhibitors. PUBLIC HEALTH RELEVANCE: Multiple myeloma (MM) remains incurable and MM cells are intrinsically resistant to traditional chemotherapeutic drugs due to the activation of IL-6 mediated growth and survival pathways. We have discovered a potent IL-6 inhibitor capable of reducing IL-6 levels in stimulated human blood and killing MM cells. This project is focused on determining the mode of action of these agents and establishing efficacy in a range of MM cells under conditions that mimic the bone marrow microenvironment.