Tumor-selective Anticancer Prodrugs

描述（由申请人提供）：基质金属蛋白酶（MMP）-2和-9的蛋白水解活性高度定位于侵袭性肿瘤的外表面。该项目的目标是合成和评估在肿瘤部位被MMP-2和MMP-9选择性切割的前药。使用直接连接和可切割的接头，我们将合成两类抗肿瘤化合物的衍生物，氨基开环环丙基苯并吲哚啉（CBLS）和阿霉素，其中短MMP-可切割的肽附加。CBI是一类非常有效的小沟结合/烷化剂，在皮摩尔浓度下显示出体外细胞毒性。多柔比星，白色，在体外效力低1000倍，是一种临床批准的药物，对许多血液和实体肿瘤具有良好的治疗特性。我们的策略利用了MMPs-2和-9的高度调节的肿瘤限制性蛋白水解活性，以及这些酶的高周转率。我们计划通过我们的体外酶测定、体外细胞毒性测定和体内治疗实验来证明MMP-底物肽基前药与其相应的母体药物相比将具有减弱的毒性、肿瘤选择性和用于治疗癌症的治疗功效。 建议的商业应用：癌症治疗仍然是最大的未满足的医疗需求之一。 许多前药策略的目标是通过选择性活化途径增加递送至肿瘤的活性药物的量。 我们提出的前药被设计成毒性显著降低，直到在肿瘤部位被肿瘤选择性酶活性重新激活。 该策略可以代表朝着区分正常和恶性细胞的目标的显著进步，并且同样地，代表癌症治疗的显著进步。

DESCRIPTION (provided by applicant): The proteolytic activity of matrix metalloproteases (MMPs)-2 and -9 is highly localized to the outer surfaces of invasive tumors. The goal of this project is to synthesize and evaluate prodrugs that are selectively cleaved by MMP-2 and -9 at the tumor site. Using both direct attachment and cleavable linkers, we will synthesize derivatives of two classes of antitumor compounds, the amino secocyclopropylbenzindolines (CBls) and doxorubicin, to which short MMP-cleavable peptides are appended. The CBIs are an extraordinarily potent class of minor groove binding/alkylating agents that show in vitro cytotoxicity at picomolar concentrations. Doxorubicin, white 1000-fold less potent in vitro, is a clinically approved drug having a well-described therapeutic profile against many hematologic and solid tumors. Our strategy takes advantage of the highly regulated, tumor-restricted proteotytic activity of MMPs-2 and -9, and the high turnover rates of these enzymes. We plan to demonstrate through our in vitro enzymatic assays, in vitro cytotoxicity assays, and in vivo therapy experiments, that MMP-substrate peptidyl prodrugs will have attenuated toxicities compared to their corresponding parent drugs, tumor selectivity, and therapeutic efficacy for the treatment of cancer. PROPOSED COMMERCIAL APPLICATION: Cancer therapy still represents one of the largest unmet medical needs. The goal of many prodrug strategies is to increase the amount of active drug delivered to a tumor through selective activation pathways. The prodrugs we propose are designed to be significantly less toxic until reactivated at the tumor site by tumor-selective enzymatic activity. this strategy could represent a significant advancement toward the goal of distinguishing between normal and malignant cells, and, as such, a significant advancement in the treatment of cancer.