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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：
10294366
负责人：
John Michael Streicher
金额：
$ 65.79万
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/10294366
关键词：
ABCB1 gene Absence of pain sensation Acute Pain Affect Affinity Analgesics Binding Proteins Bioavailable 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 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/antagonist 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.

摘要慢性疼痛的治疗在临床上具有挑战性，并且严重依赖阿片类药物，如吗啡。和羟考酮。然而，阿片类药物受到许多影响生活质量的副作用的困扰，如耐受性，便秘和奖励/成瘾，导致阿片类药物滥用、成瘾和过量使用危机。这些临床社会挑战突显了对疼痛管理新方法的巨大医学需求。为此，我们率先研究了热休克蛋白90(Hsp90)在调节阿片类药物信号中的作用转导、抗伤害性和副作用。我们发现热休克蛋白90对单位阿片受体(MOR)有调节作用。脑和脊髓中不同作用的信号转导。在大脑中，Hsp90促进MOR信号和抗伤害性感受，使Hsp90抑制在大脑中阻断阿片类抗伤害性感受。在脊髓，Hsp90可阻断更多信号转导和抗伤害性，使脊髓Hsp90抑制增强阿片类抗伤害性。在进一步的研究发现，抑制脊髓中的Hsp90可使吗啡的抗伤害性反应增强2-3倍在急性和慢性疼痛中，降低耐受性并挽救已建立的耐受性，所有这些都不会改变便秘的功效和奖赏。这些结果表明，脊髓Hsp90的抑制可以作为一种阿片类药物减量策略，在减少副作用的同时改善或维持止痛效果。然而，对这种方法的一个挑战是，我们发现，当系统地给予非选择性Hsp90抑制剂时，结果类似于大脑，阻断阿片类抗伤害性感受。在寻找绕过这个限制的方法时，我们发现 Hsp90亚型在脑和脊髓中不同，Hsp90α单独作用于脑，而Hsp90α，Hsp90β，和Grp94都在脊髓中起作用。假设一种具有异构体选择性的Hsp90抑制剂可用于靶向脊髓特异性异构体，我们发现热休克蛋白90β选择性抑制剂KUNB106增强了吗啡的抗当全身给药时，在抢救时产生伤害性的吗啡耐受性。这些结果有力地证明了提示热休克蛋白90β选择性抑制剂可作为一种新的、一流的阿片类药物减量治疗。然而，KUNB106是第一代化合物，溶解性和药代动力学(PK)较差，且不确定的治疗方案。在这份提案中，我们将优化KUNB106，以创建一种新的治疗方法加强阿片类药物治疗，减少奖励/成瘾等阿片类药物副作用。在目标1中，我们将利用尖端技术利用Hsp90异构体共结晶结构创造优化化合物的药物化学方法基于KUNB106脚手架。在目标2中，我们将测试这些化合物的Hsp90亚型选择性，ADMET 参数、靶外相互作用和小鼠体内PK，旨在识别高选择性、可溶和口服的生物可利用化合物。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效果。抗小鼠急性和慢性疼痛模型中的伤害感受，同时减少耐受性、便秘、奖励和呼吸抑制。排名靠前的候选人将接受偏离目标的副作用和毒性测试。通过这个项目，我们的目标是为进一步开发用于患者疼痛管理的新疗法创造优化的候选药物。