Antagonists of CRMP2 Phosphorylation for Chemotherapy-Induced Peripheral Neuropathy

CRMP2 磷酸化拮抗剂治疗化疗引起的周围神经病变

• 批准号: 10505802
• 负责人: Rajesh Khanna
• 金额: $ 139.49万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10505802
• 关键词: Affect; Afferent Neurons; Analgesics; Animal Model; Arizona; Binding; Biochemical; Biological Assay; Biological Sciences; Biology; Calcium; Calcium Channel; Cells; Chemicals; Chemotherapy-induced peripheral neuropathy; Clinical; Clinical Trials; Cyclin-Dependent Kinase 5; Data; Development; Disclosure; Dorsal; Drug Kinetics; Economics; Effectiveness; Electrophysiology (science); Faculty; Fentanyl; G-Protein-Coupled Receptors; Goals; Heroin; Human; In Vitro; Industry; Ion Channel; Knowledge; Laboratories; Lead; Link; Marketing; Mechanics; Modeling; Molecular; Natural Products; Neurons; Nociception; Nociceptors; Opioid; Opioid Receptor; Paclitaxel; Pain; Pain management; Pathologic; Pathway interactions; Peripheral nerve injury; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphoproteins; Phosphorylation; Phosphorylation Site; Phosphotransferases; Postoperative Pain; Productivity; Property; Public Health; Rattus; Regulation; Research; Research Personnel; Rewards; Rodent; Rodent Model; Secure; Series; Site; Sodium; Sodium Channel; Specificity; Spinal; Spinal Ganglia; Stimulus; Substantia Gelatinosa; Surface; Synapses; Synaptic Transmission; Techniques; Technology; Testing; Translating; Tumor Cell Line; United States National Institutes of Health; Universities; Up-Regulation; Validation; Work; addiction; addiction liability; analog; antagonist; axon guidance; base; chronic pain; chronic pain management; collapsin response mediator protein-2; cytotoxicity; design; dorsal horn; drug development; experimental study; falls; human female; in silico; in vivo; inhibitor; injured; invention; lead series; male; mechanical allodynia; motor impairment; mouse model; multidisciplinary; negative affect; nerve injury; neurotoxicity; neurotransmission; neurotransmitter release; novel; novel strategies; opioid epidemic; pain processing; pain reduction; painful neuropathy; pre-clinical; prescription pain reliever; presynaptic; programs; recruit; screening; side effect; small molecule; social; spared nerve; success; synergism; synthetic opioid; therapeutic development; therapeutic target; trafficking; virtual; voltage; welfare

SUMMARY Identification of new targets and mechanisms underlying neuropathic pain is critical to developing new target- specific medications for better neuropathic pain management. The misuse of and addiction to opioids—including prescription pain relievers, heroin, and synthetic opioids such as fentanyl—is a serious national crisis that affects public health as well as social and economic welfare. The current opioid crisis requires novel approaches to chronic pain management. Our proposal leverages a unique finding, originating from the laboratory of Dr. Rajesh Khanna (University of Arizona), that peripheral nerve injury-induced upregulation of an axonal guidance phosphoprotein collapsin response mediator protein 2 (CRMP2) and the N-type voltage-gated calcium (CaV2.2) as well as the NaV1.7 voltage-gated sodium channel, correlates with the development of neuropathic pain. Leveraging a pocket on the surface of CRMP2, amenable for in silico screening, the PI’s laboratory performed a virtual screen of nearly 0.3 million compounds (diverse small molecules and natural products). Several of the top 21 ‘hit’ compounds from this screen have been validated in in vitro and in vivo experiments, providing experimental proof of our in-silico predictions. Predicted physico-chemical properties of the hit series fall within ranges of lead- or ‘drug-like’ molecules. We have assembled a diverse multidisciplinary team to test the hypothesis that inhibiting CRMP2 phosphorylation associated with sodium and calcium channel activities to decrease nociceptor activity culminates in reduced pain. Our Specific Aims, guided by quantitative goals, are: (1) to profile CRMP2 phosphorylation antagonists for their ability to: (i) bind CRMP2 and (ii) block its phosphorylation by Cdk5 and (iii) inhibit calcium and sodium currents in sensory neurons using whole-cell electrophysiology with a smaller subset being tested in male/female human DRGs; (2) profile CRMP2 phosphorylation antagonists for ADME pharmacokinetic properties and off-target effects on GPCRs, kinases, ion channels and alternative known pain targets, including opioid receptors; (3) characterize the best CRMP2 phosphorylation antagonists for in vivo efficacy in rodents using a phenotypic screen and spared nerve injury (SNI) model of neuropathic pain and explore the potential of phosphorylated CRMP2 as a marker of target engagement; (4) validate optimized CRMP2 phosphorylation antagonists in a mouse model of chemotherapy- induced peripheral neuropathy (CIPN) and assess potential reward and/or aversion. At the end of our study, we expect to have at least one lead series for optimization with the goal of developing a selective and efficacious CRMP2 phosphorylation inhibitor for neuropathic pain with minimal side effects or addiction potential.

总结 识别神经病理性疼痛的新靶点和机制对于开发新靶点至关重要， 用于更好的神经性疼痛管理的特定药物。阿片类药物的滥用和成瘾----包括 处方止痛药，海洛因和合成阿片类药物，如芬太尼，是一个严重的国家危机，影响 公共卫生以及社会和经济福利。当前的阿片类药物危机需要新的方法来解决 慢性疼痛管理我们的提案利用了一个独特的发现，来自Rajesh博士的实验室。 卡纳（亚利桑那大学），即周围神经损伤诱导的轴突引导上调 磷蛋白介导蛋白2（CRMP 2）和N型电压门控钙（CaV2.2） 以及NaV1.7电压门控钠通道，与神经性疼痛的发展相关。 利用CRMP 2表面上的一个口袋，适合于计算机筛选，PI的实验室进行了一项 近30万种化合物（各种小分子和天然产物）的虚拟筛选。其中的几个 来自该筛选的21种“命中”化合物已在体外和体内实验中得到验证， 实验证明了我们的电脑预测预测的命中系列的物理化学性质落在 一系列的铅或“药物样”分子。我们组建了一个多元化的多学科团队来测试 抑制与钠和钙通道活性相关的CRMP 2磷酸化， 伤害感受器活性的降低最终导致疼痛的减轻。我们的具体目标，以量化目标为指导，是： (1)分析CRMP 2磷酸化拮抗剂的以下能力：（i）结合CRMP 2和（ii）阻断其磷酸化能力。 通过Cdk 5的磷酸化和（iii）使用全细胞抑制感觉神经元中的钙和钠电流 在男性/女性人DRG中测试较小子集的电生理学;（2）CRMP 2特征 ADME药代动力学性质和对GPCR，激酶， 离子通道和其他已知的疼痛靶点，包括阿片受体;（3）表征最佳CRMP 2 使用表型筛选和避免神经损伤的啮齿动物体内功效的磷酸化拮抗剂 (SNI)磷酸化CRMP 2作为神经病理性疼痛的靶点标记物的潜力 （4）在化疗的小鼠模型中验证优化的CRMP 2磷酸化拮抗剂- 诱发性周围神经病变（CIPN），并评估潜在的奖励和/或厌恶。在研究结束时，我们 我希望至少有一个铅系列优化的目标是开发一个选择性和有效的 CRMP 2磷酸化抑制剂用于神经性疼痛，具有最小的副作用或成瘾潜力。