Development of Hsp90 Isoform- Selective Inhibitors as a Novel Opioid Dose-Reduction Therapy

开发 Hsp90 异构体选择性抑制剂作为新型阿片类药物剂量减少疗法

基本信息

批准号：
10442661
负责人：
John Michael Streicher
金额：
$ 63.11万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10442661
关键词：
ABCB1 gene Absence of pain sensation Acute Pain Affect Affinity Analgesics Binding Proteins Biological Availability Brain Chronic Clinical Constipation Crystallization Cytochrome P450 Data Dependence Development Dose Drug Kinetics Drug usage Fluorescence Polarization Generations Goals HIV HSP 90 inhibition Health Heat-Shock Proteins 90 Human In Vitro Individual Investigation Lead Liver Microsomes MDCK cell Medical Methods Modernization Morphine Mus Neuropathy Nociception Opioid Opioid Analgesics Opioid Receptor Oral Oral Administration Overdose Oxycodone Pain Pain management Patients Performance Permeability Persons Pharmaceutical Chemistry Pharmaceutical Preparations Plasma Plasma Proteins Play Protein Isoforms Proteins Public Health Quality of life Receptor Signaling Regulation Rewards Role Signal Transduction Solubility Spinal Spinal Anesthesia Spinal Cord Structure Surgical incisions Tail Techniques Testing Therapeutic Toxic effect Toxicity Tests United States Ventilatory Depression Work addiction analog aqueous base chronic pain chronic pain management cost improved in vivo in vivo evaluation inhibitor molecular modeling morphine tolerance mu opioid receptors novel novel drug class novel strategies novel therapeutics opiate tolerance opioid abuse opioid epidemic opioid therapy pain model patient population response scaffold side effect small molecule social

项目摘要

ABSTRACT The management of chronic pain is clinically challenging, and relies heavily on opioid drugs like morphine and oxycodone. However, opioids are plagued by numerous side effects that impact quality of life, like tolerance, constipation, and reward/addiction, contributing to an opioid abuse, addiction, and overdose crisis. These clinical and social challenges highlight the vast medical need for new approaches to pain management. To this end, we have pioneered an investigation into the role of Heat shock protein 90 (Hsp90) in regulating opioid signal transduction, anti-nociception, and side effects. We have found that Hsp90 regulates mu opioid receptor (MOR) signal transduction to different effect in brain vs. spinal cord. In brain, Hsp90 promotes MOR signaling and anti- nociception, so that Hsp90 inhibition in brain blocks opioid anti-nociception. In spinal cord, Hsp90 blocks MOR signaling and anti-nociception, so that Hsp90 inhibition in spinal cord enhances opioid anti-nociception. In further studies, we found that Hsp90 inhibition in spinal cord increases morphine anti-nociceptive potency 2-3 fold in acute and chronic pain, reduces tolerance and rescues established tolerance, all without altering the potency of constipation and reward. These results suggest that spinal Hsp90 inhibition could be used as an opioid dose-reduction strategy, to improve or maintain analgesic efficacy while reducing side effects. However, one challenge to this approach is our finding that non-selective Hsp90 inhibitors, when given systemically, gave results similar to the brain, blocking opioid anti-nociception. Seeking a way around this limitation, we found that Hsp90 isoforms differ between brain and spinal cord, with Hsp90α alone acting in brain while Hsp90α, Hsp90β, and Grp94 all act in spinal cord. Hypothesizing that an isoform-selective Hsp90 inhibitor could be used to target spinal cord-specific isoforms, we found that the Hsp90β-selective inhibitor KUNB106 enhanced morphine anti- nociception while rescuing established morphine tolerance when given systemically. These results strongly suggest that Hsp90β-selective inhibitors could be used as a novel, first-in-class opioid dose-reduction therapy. However, KUNB106 is a first generation compound, with poor solubility and pharmacokinetics (PK) and an uncertain therapeutic profile. In this proposal, we will thus optimize KUNB106 to create a new therapeutic to enhance opioid therapy and reduce opioid side effects like reward/addiction. In Aim 1 we will utilize cutting edge medicinal chemistry approaches using Hsp90 isoform co-crystallized structures to create optimized compounds based on the KUNB106 scaffold. In Aim 2, we will test these compounds for Hsp90 isoform selectivity, ADMET parameters, off-target interactions, and in vivo PK in mice, aiming to identify highly selective, soluble, and orally bioavailable compounds. In Aim 3, we will test the best of these compounds for their efficacy in enhancing opioid anti-nociception in acute and chronic pain models in mice, while reducing tolerance, constipation, reward, and respiratory depression. Top candidates will be tested for off-target side effects and toxicity. Through this project, we aim to create optimized candidates for further development as new therapeutics for patient pain management.

抽象的慢性疼痛的治疗在临床上具有挑战性，并且严重依赖吗啡等阿片类药物然而，阿片类药物受到许多影响生活质量的副作用的困扰，例如耐受性、便秘和奖励/成瘾，导致阿片类药物滥用、成瘾和过量危机。社会挑战凸显了对新的疼痛管理方法的巨大医疗需求。率先研究了热休克蛋白 90 (Hsp90) 在调节阿片类信号中的作用我们发现 Hsp90 可以调节 mu 阿片受体 (MOR)。信号转导在大脑和脊髓中产生不同的效果在大脑中，Hsp90 促进 MOR 信号传导并抗- 伤害感受，因此大脑中的 Hsp90 抑制会阻断阿片类药物的抗伤害感受。在脊髓中，Hsp90 会阻断 MOR。信号传导和抗伤害感受，因此脊髓中的 Hsp90 抑制进一步增强阿片类药物的抗伤害感受。研究中，我们发现脊髓中的 Hsp90 抑制可将吗啡的抗伤害效力提高 2-3 倍在急性和慢性疼痛中减少、耐受并挽救已建立的耐受性，所有这些都不会改变这些结果表明脊髓 Hsp90 抑制可用作一种治疗方法。阿片类药物剂量减少策略，以提高或维持镇痛功效，同时减少副作用。这种方法面临的一个挑战是我们发现非选择性 Hsp90 抑制剂在全身给药时会产生与大脑相似的结果，阻断阿片类药物的抗伤害感受，寻找绕过这一限制的方法，我们发现。 Hsp90 亚型在大脑和脊髓之间有所不同，Hsp90α 单独作用于大脑，而 Hsp90α、Hsp90β、和 Grp94 均在脊髓中起作用，假设异构体选择性 Hsp90 抑制剂可用于靶向作用。脊髓特异性亚型，我们发现 Hsp90β 选择性抑制剂 KUNB106 增强吗啡抗全身给予时，可减轻伤害，同时挽救已建立的吗啡耐受性。表明 Hsp90β 选择性抑制剂可用作新型、一流的阿片类药物剂量减少疗法。然而，KUNB106是第一代化合物，溶解度和药代动力学（PK）较差，并且因此，在本提案中，我们将优化 KUNB106，以创造一种新的治疗方法。增强阿片类药物治疗并减少阿片类药物副作用（如奖励/成瘾）在目标 1 中，我们将利用尖端技术。使用 Hsp90 异构体共结晶结构的药物化学方法来创建优化的化合物基于 KUNB106 支架在目标 2 中，我们将测试这些化合物的 Hsp90 同工型选择性 ADMET。参数、脱靶相互作用和小鼠体内 PK，旨在鉴定高选择性、可溶性和口服的在目标 3 中，我们将测试这些化合物中最好的化合物在增强阿片类药物方面的功效。在小鼠急性和慢性疼痛模型中具有抗伤害作用，同时降低耐受性、便秘、奖励和通过该项目，将测试最佳候选药物的脱靶副作用和毒性。我们的目标是创造优化的候选药物，以进一步开发作为患者疼痛管理的新疗法。