Discovery of T-type Calcium Channel Antagonists from Multicomponent Reactions and Their Application in Paclitaxel-induced Peripheral Neuropathy

摘要 化疗诱导的周围神经病变（CIPN）在64%的癌症患者中检测到， 癌症。手和/或脚的感觉症状，通常是“袜子手套”模式，是常见的， 表现为疼痛、麻木和/或刺痛。CIPN可导致化疗剂量减少或 停药，也可能对生活质量产生长期影响。CIPN的课程可以是 不可预测：虽然症状可能在化疗停止后消退，但也可能持续 年自20世纪70年代引入以来，抗微管紫杉醇（Taxol®）一直被用作 对肺癌、乳腺癌、卵巢癌、白细胞减少症和肝癌有效抗癌剂。但是紫杉醇引起的 周围神经病变是紫杉醇的主要剂量限制性副作用。紫杉烷类（如紫杉醇）可能导致 周围神经的结构性损伤，导致周围神经的异常躯体感觉处理 和/或中枢神经系统。背根神经节（DRG）感觉神经元以及背根神经节中的神经元细胞 脊髓是化疗诱导神经毒性发生的关键部位。发病机制复杂， 包括离子通道的失调。例如，Paclitaxel增加了低电压激活的 大鼠DRG神经元中的T型（Cav3.2）Ca 2+通道;这些神经元负责传递有害物质 感觉刺激，表明这些通道是特定感觉异常的重要介质 与CIPN有关。T型Ca 2+通道是神经元兴奋性增加的关键决定因素， 伴随持续性神经病理性疼痛的神经传递。尽管Cav3.2在临床上已经成为目标， 尽管这些药物是小分子拮抗剂，但没有靶向这些通道的药物进入II期人体临床试验。 该提案旨在探索多组分反应产物，在PI实验室开发-Jun博士 Wang，用于快速鉴定有效的和选择性的T型Ca 2+通道拮抗剂。为了这项工作，我们 我与Rajesh卡纳博士（Regulonix，LLC的PI和首席科学官）合作， 在体外和体内功效测定以及PK优化中选择化合物及其类似物。工作 这是开发CIPN非阿片类疼痛治疗的第一步。我们期待成功 对抗紫杉醇引起的慢性疼痛也会转化为其他类型的慢性疼痛，但CIPN提供了 专注于早期概念验证。Regulonix的具体目标是：（1）UAWJ 111的设计和合成 类似物和阐明选择的UAWJ的通道特异性和生物物理性质，以获得机制 和安全性信息，并记录相关神经元细胞中功能的独特途径;（2）特征 UAWJ 111类似物的体外细胞毒性和药代动力学性质;（3）表征最佳的 来自Aim 2的两个UAWJ，用于使用神经性疼痛模型（紫杉醇）的临床前研究，以提供 关于功效的信息。在我们的研究结束时，我们希望有一个有效的UAWJ类似物， 几个有价值的备用化合物

Summary Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is detected in 64% of cancer patients during all phases of cancer. Sensory symptoms in the hands and/or feet, typically in a “stocking-glove” pattern, are common, and manifested as pain, numbness, and/or tingling. CIPN can result in chemotherapy dose reduction or discontinuation, and can also have long-term effects on the quality of life. The course of CIPN can be unpredictable: while symptoms may resolve after chemotherapy is discontinued, they can also continue for years. Since its introduction in the 1970s, the antimicrotubule Paclitaxel (Taxol®) has been used as an effective anticancer agent against lung, breast, ovarian, leukopenia and liver cancer. But, Paclitaxel-induced peripheral neuropathy is the major dose-limiting side effect of paclitaxel. Taxanes (like Paclitaxel) may cause structural damage to peripheral nerves, resulting in aberrant somatosensory processing in the peripheral and/or central nervous system. Dorsal root ganglia (DRG) sensory neurons as well as neuronal cells in the spinal cord are key sites in which chemotherapy induced neurotoxicity occurs. Pathogenesis is complex but includes dysregulation of ion channels. For example, Paclitaxel increases expression of low-voltage activated T-type (Cav3.2) Ca2+ channels in rat DRG neurons; these neurons are responsible for conveying noxious sensory stimuli, suggesting these channels are important mediators of specific sensory abnormalities associated with CIPN. T-type Ca2+ channels are critical determinants of increased neuronal excitability and neurotransmission accompanying persistent neuropathic pain. Though Cav3.2 has been targeted clinically with small molecule antagonists, no drugs targeting these channels have advanced to phase II human clinical trials. This proposal aims to explore multicomponent reaction products, developed in the laboratory of the PI - Dr. Jun Wang, for the rapid identification of potent and selective T-type Ca2+ channel antagonists. For this work, we have partnered with Dr. Rajesh Khanna (PI and Chief Scientific Officer, Regulonix, LLC) for characterizing select compounds and their analogs in in vitro and in vivo efficacy assays as well PK optimization. The work proposed here is the first step in developing non-opioid pain treatments for CIPN. We anticipate success against paclitaxel-induced chronic pain will translate into other chronic pain types as well, but CIPN provides focus for early stage proof-of-concept. Regulonix's specific aims are: (1) Design and synthesis of UAWJ111 analogs and elucidation of channel specificity and biophysical properties of select UAWJs to gain mechanistic and safety information and to document the unique pathway for function in relevant neuronal cells; (2) Profile the in vitro cellular cytotoxicity and pharmacokinetic properties of UAWJ111 analogs; (3) Characterize the best two UAWJs, from Aim 2, for preclinical studies using a neuropathic pain model (paclitaxel) to provide information about efficacy. At the conclusion of our study, we expect to have a validated UAWJ analog and several worthy backup compounds.