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(申请人提供)：化疗引起的周围神经病(CIPN)是一种常见的、通常是剂量限制的主要化疗药物的副作用，包括紫杉烷、bortezomib、长春花碱、铂化合物和新批准的治疗药物，如埃利布林。CIPN的最初症状包括四肢感觉丧失和疼痛，随后可发展为无法控制的膀胱排空、呼吸功能障碍和瘫痪。这些症状在联合治疗方案、剂量密度方案和预治疗的患者中通常会变得更糟。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%的患者减少剂量或停止某些方案的化疗(如奥沙利铂、亚叶酸钙、氟尿嘧啶)，导致更差的治疗结果。目前治疗CIPN的方法侧重于缓解特定症状，而不是根本原因。近年来，对包括CIPN在内的周围神经病的发病机制和神经生长因子(NGF)的作用已有了很大的研究进展。特别是，NGF已被证明可以预防由多种化疗药物引起的CIPN，包括紫杉烷、铂配合物和长春新碱。然而，使用人神经生长因子预防周围神经病的临床试验由于药代动力学较差而失败。我们利用最近发展起来的化学方法构建了一种名为神经免疫亲和素的新型小分子，这种小分子与伴侣蛋白FKBP52结合并直接增强NGF，我们证明了神经免疫亲和素可以在不影响体外和体内抗癌活性的情况下防止神经毒性的发生。在这项建议中，我们希望在抗癌药物存在的情况下筛选和选择更多的FKBP52结合部分，以选择进一步开发的候选药物，作为预防紫杉烷和铂络合物引起的CIPN的治疗药物。我们提出了以下目标：目的1.设计、合成和构建抑制FKBP52的神经免疫亲和素部分文库。目的2.筛选与神经营养靶标FKBP52结合的文库化合物，并在体外评估PK/PD。目的3.在原代神经细胞和周围神经细胞系中进行抗癌药物存在下的神经营养活性的体外筛选，并选择化合物。 公共卫生相关性：用于治疗癌症的药物造成的严重毒性仍然是一个严重的世界性问题。在这一领域的众多挑战中，化疗药物的严重毒性导致治疗方案提前终止，从而降低了这些方案的疗效。此外，有毒的化疗药物危害癌症患者的健康，降低患者的生活质量。Amplyx为降低化疗药物的毒性提出了一种全新的方法。我们的策略使用了免疫亲和素化合物，它可以保护健康细胞免受化疗药物的神经毒性副作用。