Discovering a Novel Immunophilin to Lower the Toxicity of Cancer Therapeutics

发现一种新型亲免素来降低癌症治疗药物的毒性

• 批准号: 8395183
• 负责人: MITCHELL W MUTZ
• 金额: $ 30.1万
• 依托单位: AMPLYX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8395183
• 关键词: Adverse effects; Antibodies; Antineoplastic Agents; Area; Aryl Hydrocarbon Hydroxylases; Binding; Bladder; Bortezomib; Cancer Patient; Cell Line; Cells; Chemicals; Chemistry; Chemotherapy-Oncologic Procedure; Clinical Trials; Complex; Computer software; Data; Development; Dose; Dose-Limiting; Drug Kinetics; Drug usage; FK506; Fluorouracil; Functional disorder; Glutamine; Goals; Growth Factor; Health; Human; Immunophilins; In Vitro; Individual; Interleukin-2; Lead; Leucovorin; Libraries; Life; Limb structure; Malignant Neoplasms; Measurement; Methods; Nerve; Nerve Growth Factors; Neurites; Neurons; Outcome; Pain; Paralysed; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Permeability; Pharmaceutical Preparations; Phase III Clinical Trials; Plant Roots; Platinum; Proteins; Quality of life; Rattus; Recombinants; Regimen; Relative (related person); Roentgen Rays; Role; Sales; Screening procedure; Sensory; Structure; Symptoms; Taxane Compound; Testing; Therapeutic; Toxic effect; Tumor Cell Line; Vinca Alkaloids; Vincristine; Vitamin E; analog; anti-cancer therapeutic; base; chaperonin; chemotherapy; design; docetaxel; dosage; gabapentin; in vivo; interest; meetings; mortality; neuroblastoma cell; neurotoxic; neurotoxicity; novel; oncology; overexpression; oxaliplatin; phase 2 study; prevent; relating to nervous system; respiratory; small molecule; success; tacrolimus binding protein 4; taxane

DESCRIPTION (provided by applicant): Chemotherapy induced peripheral neuropathy (CIPN) is a frequent and often dose limiting side effect of mainstay chemotherapeutics including taxanes, bortezomib, vinca alkaloids, platinum complexes, and newly approved therapeutics such as Eribulin. Initial symptoms of CIPN include sensory loss and pain in the extremities, and can later progress to uncontrolled bladder emptying, respiratory dysfunction, and paralysis. These symptoms generally become worse during combination therapeutic regimens, dose-dense regimens, and for pretreated patients. In addition to further lowering the quality of life fo cancer patients, neurotoxicities may cause over 33% of patients to reduce dosages or halt chemotherapy for certain regimens (oxaliplatin, leucovorin, fluorouracil, e.g.), leading to worse therapeutic outcomes. Current approaches to treating CIPN have focused on alleviating specific symptoms as opposed to the root causes. Recently, there has been great progress in understanding the mechanistic underpinnings of peripheral neuropathies including CIPN and the role of nerve growth factor (NGF). In particular, NGF has been shown to prevent the onset of CIPN caused by a wide variety of chemotherapeutics including taxanes, platinum complexes, and vincristine. However, clinical trials to prevent peripheral neuropathy using human NGF have failed due to poor pharmacokinetics. Using recently developed chemistry to build novel small molecules called neuroimmunophilins that bind to the chaperonin FKBP52 and directly potentiate NGF, we have demonstrated that neuroimmunophilins can prevent the onset of neurotoxicity without compromising anti-cancer activity both in vitro and in vivo. In this proposal we wish to screen and select additional FKBP52 binding moieties in the presence of anti-cancer agents to select a lead candidate for further development as a therapeutic to prevent CIPN caused by taxanes and platinum complexes. We propose the following aims: Aim 1. Design and synthesize and a focused library of neuroimmunophilin moieties to inhibit FKBP52. Aim 2. Screen and select library compounds for the ability to bind to FKBP52, a neurotrophic target, and assess in vitro pk/pd. Aim 3. Perform in vitro screens for neurotrophic activity in the presence of anti-cancer agents in primary nerve cells and peripheral nerve cell lines and select compounds. PUBLIC HEALTH RELEVANCE: Severe toxicity caused by drugs used to treat cancer remains a critical, worldwide problem. Among the numerous challenges in this area, the severe toxicity of chemotherapeutics causes early termination of therapeutic regimens, thereby lowering the efficacy of these regimens. In addition, toxic chemotherapeutics endanger the health of cancer patients and lower the quality of patient life. Amplyx proposes a fundamentally new method for lowering the toxicity of chemotherapeutics. Our strategy employs immunophilin compounds which can protect healthy cells from the neurotoxic side effects of chemotherapeutics.

描述（由申请人提供）：化学疗法诱导的周围神经病（CIPN）是主阶化疗的频繁且经常限制的副作用，包括紫杉虫，硼替佐米，bortezomib，Vinca balkaloids，platinum complectes，platinum complectes和New oped批准的疗法。 CIPN的初始症状包括四肢的感觉丧失和疼痛，后来可以发展为不受控制的膀胱排空，呼吸障碍和瘫痪。这些症状通常在治疗方案，剂量致密方案以及预处理患者的情况下变得更糟。除了进一步降低癌症患者的生活质量外，神经毒性还可能导致超过33％的患者减少某些方案的剂量或停止化学疗法（Oxaliptin，leucovorin，fluorouracil，例如），从而导致较差的治疗结果。当前治疗CIPN的方法集中在减轻特定症状而不是根本原因上。最近，了解包括CIPN和神经生长因子（NGF）的作用在内的周围神经病的机械基础方面取得了长足的进步。特别是，已证明NGF可以防止由多种化学治疗药引起的CIPN发作，包括紫杉烷，铂综合体和长春新碱。然而，由于药代动力学不良而导致使用人NGF的外周神经病的临床试验失败。使用最近开发的化学物质来构建与伴侣蛋白FKBP52结合并直接增强NGF的新型小分子，我们已经证明，神经免疫性蛋白可以防止神经毒性的发作，而无需损害抗癌症的抗癌活性，均可阻止抗癌活性。在此提案中，我们希望在抗癌药物存在下筛选并选择其他FKBP52结合部分，以选择进一步发育的主要候选者作为治疗方法，以防止群群落和铂金络合物引起的CIPN。我们提出以下目的：目标1。设计和合成以及聚焦的神经免疫素部分部分抑制FKBP52。 AIM 2。屏幕和选择库化合物，以与神经营养靶标的FKBP52结合并评估体外PK/PD。 AIM 3。在原代神经细胞和周围神经细胞系中的抗癌药物存在下，在体外筛选进行神经营养活性，并选择化合物。 公共卫生相关性：用于治疗癌症的药物引起的严重毒性仍然是一个关键的全球问题。在该领域的众多挑战中，化学治疗药的严重毒性会引起治疗方案的早期终止，从而降低了这些方案的功效。此外，有毒化学治疗剂危害癌症患者的健康并降低患者生活质量。 Amplyx提出了一种从根本上降低化学疗法毒性的新方法。我们的策略采用免疫素化合物，可以保护健康细胞免受化学疗法的神经毒性副作用。