PDZ-targeted Therapeutics for Cervical Cancer

描述(申请人提供)：人类乳头瘤病毒(HPV)的致癌变异与宫颈癌的相关频率为99%，还会导致阴茎癌、肛门癌和头颈癌。我们最近确定，所有致癌的E6蛋白都与MAGI1蛋白的第一个PDZ结构域结合，这种相互作用对于HPV诱导的癌症发生和维持HPV阳性细胞的癌变状态都是至关重要的。我们已经鉴定出一种新型的先导小分子抑制剂(AVC-7)，它可以抑制E6癌蛋白与MAGI1-PDZ1之间的相互作用。阻断E6/MAGI1-PDZ1的相互作用导致E6和E7癌蛋白的下调，肿瘤抑制基因P53的恢复，并诱导宫颈癌细胞株的凋亡。在这笔赠款中，Arbor Vita提议识别更有效的AVC-7衍生物，并在体外和体内证明这些衍生物在治疗宫颈癌方面的疗效。具体地说，Arbor Vita建议(1)设计AVC-7的衍生物，使其与MAGI1结合的效力更高，并改善水溶性，(2)展示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)展示最有希望的化合物在小鼠异种移植瘤模型中的功效。该赠款的成功完成将导致E6/MAGI1-PDZ1相互作用的10 mM(或更好)抑制剂，该抑制剂选择性地诱导HPV阳性癌细胞的凋亡，并显著减少小鼠异种移植模型中的肿瘤生长。在这项建议之后，将进行第二阶段的申请，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类临床测试。 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表征了致癌HPV E6蛋白的一个新靶点MAGI1，并发现了早期的先导药物，可以降低导致E6癌蛋白的癌症水平，同时恢复p53肿瘤抑制蛋白的水平。P53是一种保护细胞免受癌变的关键蛋白质。

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.