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

• 批准号: 10592064
• 负责人: John Michael Streicher
• 金额: $ 6.79万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10592064
• 关键词: Acute Pain; Analgesics; Brain; Clinical; Constipation; Crystallization; Development; Dose; Drug Kinetics; Generations; HSP 90 inhibition; Heat-Shock Proteins 90; Human; Investigation; Medical; Morphine; Mus; Nociception; Opioid; Oral; Overdose; Oxycodone; Pain management; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Protein Isoforms; Quality of life; Receptor Signaling; Rewards; Role; Signal Transduction; Solubility; Spinal; Spinal Cord; Structure; Testing; Therapeutic; Toxic effect; Ventilatory Depression; Work; addiction; base; chronic pain; chronic pain management; improved; in vivo; inhibitor; morphine tolerance; mu opioid receptors; novel; novel strategies; novel therapeutics; opioid abuse; opioid therapy; pain model; scaffold; side effect; social

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 慢性疼痛的管理在临床上具有挑战性，并且严重依赖吗啡等阿片类药物 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， 便秘和奖赏/成瘾，导致阿片类药物滥用、成瘾和过量危机。这些临床 和社会挑战突出了对疼痛管理新方法的巨大医疗需求。为此我们 率先研究了热休克蛋白90（Hsp 90）在调节阿片信号中的作用 转导、抗伤害感受和副作用。我们发现热休克蛋白90调节μ阿片受体（莫尔）， 信号转导在脑与脊髓中具有不同作用。在脑内，Hsp 90促进莫尔信号传导和抗- 伤害感受，从而脑中的Hsp 90抑制阻断阿片样物质抗伤害感受。在脊髓中，Hsp 90阻断莫尔 信号传导和抗伤害感受，使得脊髓中的Hsp 90抑制增强阿片类抗伤害感受。进一步 研究中，我们发现脊髓中的Hsp 90抑制使吗啡抗伤害感受效力增加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 便秘和奖励的效力。这些结果表明，脊髓Hsp 90抑制可用作治疗脊髓损伤的药物。 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。然而，在这方面， 对这种方法的一个挑战是我们发现，当全身给予非选择性Hsp 90抑制剂时， 结果类似于大脑，阻断阿片类抗伤害感受。在寻找绕过这一限制的方法时，我们发现， Hsp 90亚型在脑和脊髓之间不同，Hsp 90 α单独作用于脑，而Hsp 90 α，Hsp 90 β， 和Grp 94均在脊髓中起作用。假设异构体选择性Hsp 90抑制剂可用于靶向 脊髓特异性亚型，我们发现Hsp 90 β选择性抑制剂KUNB 106增强吗啡抗脊髓特异性亚型， 当全身给予时，在挽救建立的吗啡耐受的同时的伤害感受。这些结果强烈 表明Hsp 90 β选择性抑制剂可用作新型的一流阿片类药物剂量减少疗法。 然而，KUNB 106是第一代化合物，溶解性和药代动力学（PK）差， 不确定的治疗特征。因此，在本提案中，我们将优化KUNB 106，以创造一种新的治疗方法， 加强阿片类药物治疗，减少阿片类药物的副作用，如奖励/成瘾。在目标1中，我们将利用尖端技术 使用Hsp 90同种型共结晶结构来产生优化化合物的药物化学方法 基于KUNB 106支架。在目标2中，我们将测试这些化合物的Hsp 90亚型选择性，ADMET 参数、脱靶相互作用和小鼠体内PK，旨在鉴定高度选择性、可溶性和口服的 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 在小鼠的急性和慢性疼痛模型中的抗伤害感受，同时降低耐受性、便秘、奖赏和 呼吸抑制最佳候选人将接受脱靶副作用和毒性测试。通过这个项目， 我们的目标是创造优化的候选药物，以进一步开发为患者疼痛管理的新疗法。