Discovering a Novel Immunophilin to Lower the Toxicity of Cancer Therapeutics

描述（由申请人提供）：化疗引起的周围神经病变（CIPN）是主要化疗药物（包括紫杉烷、硼替佐米、长春花生物碱、铂配合物和新批准的治疗药物如艾里布林）的常见且经常限制剂量的副作用。CIPN的初始症状包括感觉丧失和四肢疼痛，后来可发展为膀胱排空失控、呼吸功能障碍和瘫痪。这些症状通常在联合治疗方案、剂量密集方案和预先治疗的患者中变得更糟。除了进一步降低癌症患者的生活质量外，神经毒性可能导致超过33%的患者减少剂量或停止某些方案的化疗（例如奥沙利铂、亚叶酸钙、氟尿嘧啶），导致更差的治疗结果。目前治疗CIPN的方法侧重于减轻具体症状，而不是根本原因。近年来，对包括CIPN在内的周围神经病变的机制基础和神经生长因子（NGF）的作用的理解取得了很大进展。特别是，NGF已被证明可以预防多种化疗药物（包括紫杉烷、铂配合物和长春新碱）引起的CIPN的发生。然而，使用人NGF预防周围神经病变的临床试验由于药代动力学不佳而失败。利用最近开发的化学技术，我们构建了一种新的小分子，称为神经免疫亲和蛋白，它与伴侣蛋白FKBP52结合并直接增强NGF，我们已经证明，神经免疫亲和蛋白可以在不影响体外和体内抗癌活性的情况下预防神经毒性的发生。在本提案中，我们希望在抗癌药物存在的情况下筛选和选择额外的FKBP52结合片段，以选择进一步开发的主要候选物，作为预防紫杉烷和铂配合物引起的CIPN的治疗药物。我们提出以下目标：目标1。设计合成抑制FKBP52的神经亲免疫蛋白片段库。目标2。筛选和选择与FKBP52（一种神经营养靶点）结合的文库化合物，并评估体外pk/pd。目标3。在原代神经细胞和周围神经细胞系中进行抗肿瘤药物存在的体外神经营养活性筛选，并选择化合物。

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.