PDZ-targeted Therapeutics for Cervical Cancer

PDZ 靶向治疗宫颈癌

• 批准号: 7910783
• 负责人: Michael Paul Belmares
• 金额: $ 20.86万
• 依托单位: ARBOR VITA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7910783
• 关键词: Affect; Anus; Apoptosis; Binding; Biological; Cancer Etiology; Cancer cell line; Cancerous; Cells; Cervical; Cessation of life; Chemicals; Clinical; Development; Disease; Dose; Down-Regulation; Drug Formulations; Frequencies; Grant; Head and Neck Cancer; Head and neck structure; Hela Cells; Human; Human Papilloma Virus Vaccine; Human Papillomavirus; In Vitro; Induction of Apoptosis; Inhibitory Concentration 50; Interruption; Intervention; Lead; Maintenance; Malignant Neoplasms; Malignant neoplasm of anus; Malignant neoplasm of cervix uteri; Mammalian Cell; Mediating; Modeling; Modification; Molecular; Mus; Names; Normal Cell; Oncogene Proteins; Oncogenic; Oncornaviruses; Pharmaceutical Preparations; Phase; Property; Protein p53; Proteins; Publishing; Structure; Structure-Activity Relationship; TP53 gene; Therapeutic; Toxic effect; Toxicology; Tumor Suppressor Proteins; Tumor Volume; Vaccines; Variant; Water; Woman; Work; Xenograft Model; arborvitae; base; cancer cell; carcinogenesis; cell transformation; clinically significant; design; follow-up; human RCN2 protein; improved; in vivo; inhibitor/antagonist; novel; prevent; prophylactic; public health relevance; research clinical testing; restoration; small molecule; therapeutic target; tumor growth; tumor xenograft; tumorigenesis; virus related cancer; water solubility

DESCRIPTION (provided by applicant): Oncogenic variants of human papilloma virus (HPV) have been correlated with cervical cancer at a frequency of > 99%, and also cause penile, anal and head and neck cancers. We have recently determined that all oncogenic E6 proteins bind to the first PDZ domain of MAGI1 protein, an interaction that is critical for both HPV-induced carcinogenesis and for maintenance of the cancerous state in HPV-positive cells. We have identified a novel lead small molecule inhibitor (AVC-7) of the interaction between E6 oncoprotein and MAGI1- PDZ1. Interruption of the E6 / MAGI1-PDZ1 interaction results in down regulation of E6 and E7 oncoproteins, restoration of the tumor suppressor p53, and induction of apoptosis in cervical cancer cell lines. In this grant, Arbor Vita proposes to identify more potent derivatives of AVC-7 and to demonstrate the efficacy of these derivatives in treatment of cervical cancer in vitro and in vivo. Specifically, Arbor Vita proposes to (1) Design derivatives of AVC-7 with increased potency in binding to MAGI1 and improved water solubility, (2) Demonstrate the selective biological activity of AVC-7 derivatives in cultured HPV-positive cervical cancer cells, and (3) Demonstrate efficacy of the most promising compound in a murine xenograft tumor model. Successful completion of the grant will result in a 10 mM (or better) inhibitor of the E6 / MAGI1-PDZ1 interaction that selectively induces apoptosis in HPV-positive cancer cells and significantly decreases tumor growth in the murine xenograft model. This proposal will be followed by a Phase 2 application to advance a lead compound towards human clinical testing via PK/PD studies, GLP toxicology studies, and GMP drug manufacturing and formulation. PUBLIC HEALTH RELEVANCE: HPV-related cancers such as cervical, anal, penile, and head and neck are serious disorders that affect hundreds of thousands of people and for which there are no approved drugs directed at the underlying cause. Arbor Vita has characterized a novel target of the oncogenic HPV E6 proteins named MAGI1, and has identified early lead drugs that can reduce levels of cancer causing E6 oncoproteins while restoring levels of the p53 tumor suppressor. p53 is a key protein that protects cells from becoming cancerous.

描述（由申请人提供）：人乳头状瘤病毒 (HPV) 的致癌变体与宫颈癌的发生率 > 99% 相关，并且还会导致阴茎癌、肛门癌和头颈癌。我们最近确定，所有致癌 E6 蛋白均与 MAGI1 蛋白的第一个 PDZ 结构域结合，这种相互作用对于 HPV 诱导的癌发生和 HPV 阳性细胞的癌状态的维持至关重要。我们已经确定了 E6 癌蛋白和 MAGI1-PDZ1 之间相互作用的新型先导小分子抑制剂 (AVC-7)。 E6 / MAGI1-PDZ1 相互作用的中断会导致 E6 和 E7 癌蛋白的下调、肿瘤抑制因子 p53 的恢复以及宫颈癌细胞系细胞凋亡的诱导。在这笔资助中，Arbor Vita 提议鉴定更有效的 AVC-7 衍生物，并证明这些衍生物在体外和体内治疗宫颈癌的功效。具体而言，Arbor Vita 建议：(1) 设计 AVC-7 衍生物，提高与 MAGI1 结合的效力并改善水溶性，(2) 证明 AVC-7 衍生物在培养的 HPV 阳性宫颈癌细胞中的选择性生物活性，以及​​ (3) 证明最有前途的化合物在鼠异种移植肿瘤模型中的功效。成功完成资助将产生一种 10 mM（或更好）的 E6 / MAGI1-PDZ1 相互作用抑制剂，选择性诱导 HPV 阳性癌细胞凋亡，并显着降低小鼠异种移植模型中的肿瘤生长。该提案之后将进行第二阶段申请，通过 PK/PD 研究、GLP 毒理学研究以及 GMP 药物制造和配方，将先导化合物推向人体临床测试。 公共卫生相关性：与 HPV 相关的癌症，如宫颈癌、肛门癌、阴茎癌和头颈癌，是影响数十万人的严重疾病，目前还没有针对根本原因的批准药物。 Arbor Vita 确定了致癌 HPV E6 蛋白的新靶标 MAGI1，并确定了早期先导药物，可以降低致癌 E6 癌蛋白的水平，同时恢复 p53 肿瘤抑制因子的水平。 p53 是保护细胞免于癌变的关键蛋白质。