Chemotherapeutic Agents with Enhanced Selectivity for the Tumor Microenvironment

描述（由申请人提供）：在当今世界，发现和开发对肿瘤微环境具有增强选择性的新型癌症治疗药物仍然是一个重要而具有挑战性的目标。血管破坏剂（VDAs）是一种化合物，它可以有效地选择性地破坏肿瘤血管系统，同时保持健康细胞的血液供应完整。这些化合物有效地破坏了流向肿瘤的血液，从而使肿瘤缺乏必要的营养和氧气。这有可能最终导致肿瘤死亡。虽然许多vda正在进行人体临床试验，但迄今为止，还没有一种vda获得美国食品和药物管理局（FDA）的批准。这些化合物中的某些通过抑制微管蛋白组装成微管而起作用，从而引起肿瘤血管内内皮细胞的形态学改变。这引发了一连串的细胞信号事件，导致了对肿瘤供血血管的灾难性破坏。在本提案中提出的研究侧重于高度协作，多学科的方法来合成和快速生物学评价有前途的新型vda。结合合成/药物化学来制备新设计的化合物，再加上快速的生化和生物学评估，包括肿瘤成像（BLI和MRI），将为发现新的和改进的vda提供一个强大的平台。重要的是，这种类型的研究可能最终转化为临床，提供额外的化疗药物，增强对肿瘤微环境的选择性。

DESCRIPTION (provided by applicant): The discovery and development of new treatment agents for cancer that demonstrate enhanced selectivity for the tumor microenvironment continues to be an important and challenging goal in today's world. Vascular disrupting agents (VDAs) are compounds that are effective at selectively damaging the tumor vasculature while leaving the blood supply to healthy cells intact. These compounds effectively disrupt blood flow to tumors thus starving them of necessary nutrients and oxygen. This has the potential to ultimately lead to tumor death. While a number of VDAs are in human clinical trials, none have reached approval by the Food and Drug Administration (FDA), to date. Certain of these compounds function by inhibiting the assembly of tubulin into microtubules, thus causing morphology changes to the endothelial cells lining the tumor vasculature. This triggers a cascade of cell signaling events that results in catastrophic damage to the vessels feeding the tumor. The research presented in this proposal focuses on a highly collaborative, multidisciplinary approach to the synthesis and rapid biological evaluation of promising new VDAs. A combination of synthetic/medicinal chemistry to prepare newly designed compounds coupled with rapid biochemical and biological evaluation, including tumor imaging (BLI and MRI), will provide a strong platform for the discovery of new and improved VDAs. Importantly, this type of research may ultimately translate to the clinic providing additional chemotherapeutic agents that have enhanced selectivity towards the tumor microenvironment.