Design and synthesis of stabilized pironetin analogs for the treatment of resistant ovarian cancers

 描述（由申请人提供） 美国癌症协会估计，2015年将有超过21，290名女性被诊断患有卵巢上皮癌，五年生存率将低于50%。美国国家癌症研究所估计，80%的卵巢上皮癌患者在一线铂类和紫杉烷类化疗后复发。Nikas及其同事已经证明，编码α-微管蛋白的基因TUBA 3C在一线化疗后的短期卵巢癌幸存者中过表达。改变微管动力学的药物是一些最成功的抗癌剂，然而目前FDA批准的所有微管蛋白结合剂都靶向β-微管蛋白，并与耐药性相关。鉴于微管蛋白结合抗癌剂的总体成功，α-微管蛋白是一种有吸引力的替代药物靶标，可满足紫杉烷和铂类耐药卵巢癌新治疗的迫切需求。天然产物吡柔酮被鉴定为有效的抗增殖剂，具有针对耐药卵巢癌细胞系的低纳摩尔GI 50值。已确定吡柔酮与α-微管蛋白的Lys 352共价结合。虽然吡罗酮显示出强大的 在体外活性方面，唯一报道的体内研究导致适度的活性，伴随着严重的体重减轻，表明吡柔酮具有非常差的药代动力学/药效学性质和可能的脱靶结合。该研究金提案将检验以下假设：吡罗酮的快速代谢抑制体内疗效，合成性阻断代谢位点并开发肿瘤靶向方法将产生具有改善的PK/PD特性的治疗剂。方法包括在基于细胞的测定中使用对当前治疗剂敏感和耐受的细胞合成和评价吡柔酮类似物（Aim 1），建立概念验证抗体-吡柔酮缀合物（Aim 2），以及在体内评价类似物和缀合物（Aim 3）。这项拟议的工作将有助于实现开发有效对抗耐药卵巢癌的新型疗法的长期目标。本提案的目的是通过合成可用于进一步了解α-微管蛋白在卵巢癌中的作用的吡柔酮类似物和抗体-药物缀合物，证明α-微管蛋白是耐药卵巢蛋白癌的可行靶标。这一目标与NIH的使命一致，即支持旨在开发癌症和其他疾病最先进治疗方法的研究。

 DESCRIPTION (provided by applicant) The American Cancer Society estimates that in 2015 more than 21,290 women will be diagnosed with ovarian epithelial cancer and that the five-year survival rate will be less than 50%. The National Cancer Institute estimates that 80% of ovarian epithelial cancer patients relapse following first-line platinum- and taxane-based chemotherapy. Nikas and coworkers have shown that the gene encoding α-tubulin, TUBA3C, is overexpressed in short-term ovarian cancer survivors following first-line chemotherapy. Drugs that alter microtubule dynamics are some of the most successful anticancer agents, however all tubulin-binding agents currently approved by the FDA target β-tubulin and are associated with drug resistance. Given the overall success of tubulin-binding anticancer agents, α-tubulin is an attractive alternative drug target that would address the critical need for new treatments for taxane and platinum drug resistant ovarian cancers. The natural product pironetin was identified as a potent antiproliferative agent with low nanomolar GI50 values against resistant ovarian carcinoma cell lines. It was determined that pironetin covalently binds to Lys352 of α-tubulin. While pironetin displays potent in vitro activity, the only reported in vivo study resulted in modest activity accompanied by severe weight loss, suggesting that pironetin has very poor pharmacokinetic/pharmacodynamic properties and possible off-target binding. This fellowship proposal will test the hypothesis that rapid metabolism of pironetin inhibits in vivo efficacy and synthetically blocking the sites of metabolism and developing a tumor-targeting approach will generate therapeutic agents with improved PK/PD properties. Methods include synthesizing and evaluating analogs of pironetin in cell based assays using cells both sensitive and resistant to current therapeutics (Aim 1), establishing a proof-of-concept antibody-pironetin conjugate (Aim 2), and evaluating analogs and conjugates in vivo (Aim 3). This proposed work will help to achieve the long-term goal of developing novel therapeutics that will be effective against resistant ovarian cancers. The objective of this proposal is to demonstrate that α-tubulin is a viable target for resistant ovarin cancers by synthesizing analogs and antibody-drug conjugates of pironetin that can be used to further understand the role of α-tubulin in ovarian cancer. This goal is aligned with the mission f the NIH to support research aimed at developing state-of-the-art treatments for cancer and other diseases.