Itraconazole Analogues to Treat Medulloblastoma

伊曲康唑类似物治疗髓母细胞瘤

• 批准号: 9186528
• 负责人: Matthew Kyle Hadden
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-12 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9186528
• 关键词: Accounting; Adverse effects; Antifungal Agents; Apoptosis; Basal cell carcinoma; Binding; Biological Assay; CYP3A4 gene; Cancer Biology; Characteristics; Child; Childhood Brain Neoplasm; Clinical; Cytochrome P450; Cytochrome a; Data; Development; Diet Monitoring; Drug Interactions; Drug Kinetics; Drug Monitoring; Embryonic Development; Ensure; Enzymes; Ergosterol; Erinaceidae; Evaluation; Exhibits; Future; Goals; Growth; High Dose Chemotherapy; Human; In Vitro; Itraconazole; Lanosterol; Lead; Link; Malignant Neoplasms; Malignant neoplasm of central nervous system; Mediating; Methodology; Mind; Modeling; Modification; Molecular Target; Mus; Mutation; Oncogenic; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Point Mutation; Preparation; Property; Public Health; Radiation; Regimen; Relapse; Research; Resistance; Resistance development; Signal Pathway; Solubility; Structure-Activity Relationship; Survival Rate; Therapeutic; Tissues; Toxic effect; Triazoles; analog; base; cell type; cellular targeting; clinical application; clinical development; clinically relevant; design; improved; in vitro activity; in vivo; inhibitor/antagonist; medulloblastoma; member; mouse model; mutant; novel therapeutics; pre-clinical; preclinical evaluation; professor; public health relevance; scaffold; small molecule; small molecule inhibitor; smoothened signaling pathway; tumor

DESCRIPTION (provided by applicant): The hedgehog (Hh) pathway is a developmental signaling pathway that plays a key role in directing growth and tissue patterning during embryonic development. Dysregulation of Hh signaling contributes to the development of a variety of human tumors, most notably basal cell carcinoma (BCC) and medulloblastoma (MB). A small molecule inhibitor of Hh signaling, GDC-0449, was recently approved for the treatment of advanced BCC, providing evidence that this pathway has clinical relevance. GDC-0449 binds and inhibits smoothened (Smo), a key regulator of the pathway that is the cellular target of multiple small molecule Hh pathway inhibitors in pre-clinical and clinical development; however, mutations in Smo resulted in forms of MB resistant to GDC-0449, highlighting the need for continued development of Hh pathway inhibitors. Itraconazole (ITZ), a member of the triazole class of antifungal agents, was recently identified as a potent inhibitor of Hh signaling in vitro and in vivo (IC50 values = 270 - 690 nM). Most importantly, ITZ maintains inhibitory activity against multiple mutant forms Smo that confer resistance to GDC-0449 and prolongs survival of mice with GDC-0449 resistant forms of MB. Despite its promising anti-Hh activity, ITZ exhibits poor solubility and inhibits CYP3A4, a detrimental side effect that results in multiple drug-drug interactions and requires careful monitoring of diet and drug regimens when ITZ is administered. Preliminary structure-activity relationship (SAR) studies for ITZ-mediated Hh inhibition performed in the Hadden lab have identified multiple regions of the ITZ scaffold that are amenable to modification. Our data suggests that further modifications to these regions will provide ITZ analogues that maintain potent or enhanced Hh inhibition, while also demonstrating improved pharmacokinetic parameters and reduced off-target side effects characteristic of ITZ treatment. The overall goal of the studies described in this proposal is to develop a class of improved Hh pathway inhibitors based on the ITZ scaffold as potential anti-cancer chemotherapeutics. With respect to this central tenet, a collaborative group of medicinal chemists and cancer biologists will undertake the following specific aims: (1) synthesize and characterize ITZ analogues designed to target the Hh signaling pathway, (2) evaluate the in vitro activity of ITZ analogues prepared in Aim 1, and (3) evaluate the in vivo activity of lead IT analogues in murine models of Hh-dependent cancer. The identification of ITZ as an Hh pathway inhibitor has opened a new avenue of exploration into potential therapeutic applications of this clinically efficacious antifungal and represents a unique scaffold for the design, synthesi, and evaluation of a new class of Hh pathway inhibitors.

描述（由申请人提供）：刺猬（Hh）通路是一种发育信号通路，在胚胎发育期间指导生长和组织模式形成中起关键作用。Hh信号转导的失调有助于多种人类肿瘤的发展，最显著的是基底细胞癌（BCC）和成神经管细胞瘤（MB）。Hh信号传导的小分子抑制剂GDC-0449最近被批准用于治疗晚期BCC，提供了该途径具有临床相关性的证据。GDC-0449结合并抑制smoothened（Smo），Smo是该途径的关键调节因子，是临床前和临床开发中多种小分子Hh途径抑制剂的细胞靶点;然而，Smo突变导致MB形式对GDC-0449耐药，突出了继续开发Hh途径抑制剂的必要性。伊曲康唑（ITZ）是三唑类抗真菌剂的一员，最近被鉴定为体外和体内Hh信号传导的有效抑制剂（IC 50值= 270 - 690 nM）。最重要的是，ITZ保持对多种突变形式Smo的抑制活性，所述突变形式Smo赋予对GDC-0449的抗性，并使具有GDC-0449抗性形式的MB的小鼠存活率降低。尽管ITZ具有很好的抗Hh活性，但其溶解度较差，并抑制CYP 3A 4，这是一种有害的副作用，导致多种药物相互作用，并且在施用ITZ时需要仔细监测饮食和药物方案。在Hadden实验室中进行的ITZ介导的Hh抑制的初步结构-活性关系（SAR）研究已经确定了ITZ支架的多个区域可以进行修饰。我们的数据表明，对这些区域的进一步修饰将提供维持有效或增强的Hh抑制的ITZ类似物，同时还证明了ITZ治疗的特征性的改善的药代动力学参数和降低的脱靶副作用。 本提案中描述的研究的总体目标是开发一类基于ITZ支架的改进的Hh通路抑制剂作为潜在的抗癌化疗药物。关于这一中心原则，一个由药物化学家和癌症生物学家组成的合作小组将承担以下具体目标：（1）合成和表征旨在靶向Hh信号通路的ITZ类似物，（2）评估目标1中制备的ITZ类似物的体外活性，以及（3）评估先导IT类似物在Hh依赖性癌症小鼠模型中的体内活性。ITZ作为Hh通路抑制剂的鉴定为探索这种临床有效的抗真菌剂的潜在治疗应用开辟了新的途径，并代表了一类新的Hh通路抑制剂的设计、合成和评价的独特支架。