Regulators of NaV1.7 Channels: Novel Anti-Allodynic Drug Candidates

NaV1.7 通道的调节剂：新型抗异常疼痛候选药物

• 批准号: 9336108
• 负责人: Rajesh Khanna
• 金额: $ 30万
• 依托单位: REGULONIX, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336108
• 关键词: Action Potentials; Adverse effects; Affect; Afferent Neurons; Amitriptyline; Animals; Arizona; Baclofen; Benzamides; Binding; Biological Assay; Calcium; Calcium Channel; Caliber; Cardiac; Cells; Chemotherapy-Oncologic Procedure; Chemotherapy-induced peripheral neuropathy; Chronic; Clinical; Complex; Complication; Coupled; Development; Docking; Dose-Limiting; Drug Targeting; Dysesthesias; Effectiveness; Enzymes; Exhibits; Gel; Generations; Genetic; Human; In Vitro; Ion Channel; Lead; Legal patent; Literature; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical; Medication Management; Memory; Modeling; Morphine; Motor; Neuraxis; Neurites; Neurologic; Neurons; Neuropathy; Nociceptors; Numbness; Opioid; Oral; Paclitaxel; Pain; Paresthesia; Pathogenesis; Pathway interactions; Patients; Performance; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Pharmacotherapy; Phase; Play; Prevalence; Property; Protein Isoforms; Proteins; Quality of life; Rattus; Recommendation; Regimen; Regulation; Reporting; Risk; Safety; Semaphorin-3A; Sensory; Shock; Signal Pathway; Signal Transduction; Site; Small Business Technology Transfer Research; Smell Perception; Sodium; Sodium Channel; Specificity; Spinal Cord; Spinal Ganglia; Surface; Survival Rate; Syndrome; Technology; Testing; Therapeutic; Toxic effect; Treatment Protocols; Tricyclic Antidepressive Agents; Tubulin; Ubiquitin; Universities; Weight Gain; addiction; benzimidazole analog; biophysical properties; cancer pain; cancer survival; cancer therapy; chemotherapeutic agent; chemotherapy; chronic pain; design; drug candidate; duloxetine; experience; gabapentin; improved; in vivo; inhibitor/antagonist; motor impairment; mutant; nanomolar; neurotoxic; neurotoxicity; novel; novel therapeutics; opioid use; painful neuropathy; pre-clinical; preclinical efficacy; prevent; response; small molecule; somatosensory; success; voltage

PROJECT SUMMARY Chemotherapy-induced peripheral neuropathy (CIPN) is a common (prevalence 10–100%) and potentially dose-limiting side effect of many cancer chemotherapy drug treatment regimens. Clinically, CIPN presents with pain that is burning, shooting or electric-shock-like. The increase in prevalence of cancer coupled with an increase in the cancer survival rates due to chemotherapy regimens is transforming cancer pain into a large, unmet medical problem. Neurotoxic chemotherapeutic agents (e.g., antimicrotubule agents 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 the preferential sites in which chemotherapy induced neurotoxicity occurs. Pathogenesis is complex but includes alterations in ion channels and ectopic activation of nociceptors. For example, paclitaxel- induced chemotherapy increases the excitability of DRG neurons with a commensurate increase in NaV1.7, a voltage-gated sodium channel. NaV1.7 is expressed in both large and small diameter DRG neurons and in most functionally identified nociceptors. Of the nine Na+ channel isoforms, NaV1.7 plays a key role in setting the threshold for action potential generation in primary sensory neurons. Genetic and functional studies have established NaV1.7 as a major contributor to pain signaling in humans. NaV1.7 has been difficult to target selectively over other voltage-gated sodium channels due to high sequence similarity between isoforms. Therefore, alternative approaches are still needed for developing drugs targeting NaV1.7. Regulonix LLC's approach has the potential to be a paradigm shift because we are targeting NaV1.7 indirectly by focusing on a signaling pathway that controls surface expression and activity of this channel. From the calcium channel pain therapeutics literature it is clear that no one drug is efficacious in relieving pain in all patients. Whether this also holds true for current NaV1.7 drugs is an open question. Thus, development of a `third' generation of NaV1.7 “inhibitors”, such as the Regulators of NaV channels (i.e. ReNs) proposed here, is needed. Regulonix objectives in this STTR are to identify ReNs that exhibit more efficacious and safer profiles than current drugs for CIPN and that display extended durations of action. Doing so allows for a phase II STTR application for the IND-enabling studies of a selected ReN. Regulonix's specific aims are: (1) To elucidate channel specificity and biophysical properties of select ReNs to gain mechanistic and safety information and to document the unique pathway for function in relevant neuronal cells; (2) To validate the drug properties of optimized ReNs both in vitro and in vivo; and (3) to identify optimized ReNs for preclinical efficacy using a pain model (CIPN) and determine neurological side-effects (motor impairment, memory, weight gain, and smell) that provide information about efficacy and functional toxicity. At the conclusion of our study, we expect to have a validated ReN and worthy backup compounds.

项目摘要 化疗引起的周围神经病变（CIPN）是一种常见的（患病率10-100%）， 许多癌症化疗药物治疗方案的剂量限制性副作用。临床上，CIPN表现为 烧灼感、刺痛感或电击样疼痛。癌症发病率的增加， 由于化疗方案导致的癌症存活率的增加正在将癌症疼痛转化为大的， 未解决的医疗问题神经毒性化疗剂（例如，抗微管剂如紫杉醇）可 引起周围神经的结构损伤，导致周围神经中异常的躯体感觉处理 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 脊髓是化疗诱导的神经毒性发生的优先部位。发病机制 复杂，但包括离子通道的改变和伤害感受器的异位激活。例如，紫杉醇- 诱导的化疗增加了DRG神经元的兴奋性，NaV1.7相应增加， 电压门控钠通道NaV1.7在大直径和小直径DRG神经元中表达，并且在神经元中表达。 大多数功能鉴定的伤害感受器。在九种Na+通道亚型中，NaV1.7在设置通道中起关键作用。 初级感觉神经元动作电位产生的阈值。基因和功能研究 确立了NaV1.7作为人类疼痛信号传导的主要贡献者。NaV1.7很难瞄准 由于同种型之间的高度序列相似性，其相对于其他电压门控钠通道选择性地被抑制。 因此，仍然需要替代方法来开发靶向NaV1.7的药物。Regulonix LLC的 这种方法有可能成为一种范式转变，因为我们通过关注 控制该通道的表面表达和活性的信号通路。从钙通道疼痛 治疗学文献很明显，没有一种药物能有效地缓解所有患者的疼痛。这是否也 是否适用于目前的NaV1.7药物是一个悬而未决的问题。因此，开发“第三代”NaV1.7 需要“抑制剂”，例如本文提出的NaV通道的调节剂（即ReN）。Regulonix 本STTR的目的是鉴定比现有药物更有效、更安全的ReN 并显示延长的动作持续时间。这样做允许第二阶段STTR应用于 选定ReN的IND使能研究。Regulonix的具体目标是：（1）阐明通道特异性 和生物物理特性，以获得机械和安全信息，并记录 在相关神经元细胞中发挥作用的独特途径;（2）验证优化的ReNs的药物性质 在体外和体内;以及（3）使用疼痛模型（CIPN）鉴定用于临床前功效的优化的ReN 并确定神经副作用（运动障碍，记忆，体重增加和嗅觉）， 关于功效和功能毒性的信息。在我们的研究结束时，我们希望有一个有效的 ReN和有价值的备份化合物。