Inhibitor mediated protein degradation

描述（由申请人提供）：存在用于在转录水平上操纵蛋白质表达的强大工具包，但是用于蛋白质的翻译后调节的方法很少并且效用有限。诱导内源性蛋白质降解的小分子显然是探测蛋白质功能的非常有用的工具，也是一种令人兴奋的化疗方法。挑战在于开发生物相容性和广泛适用的技术。我们偶然发现了一个部分，当与识别元件结合时，诱导靶蛋白的降解。我们建议描述这种现象，并开发这些新的蛋白质敲除工具，这将是非常宝贵的，在广泛的生物和制药应用。 公共卫生相关性：操纵蛋白质水平的能力在生物功能的研究中是无价的，因此如果成功，这项提议将产生巨大的影响。 在基础科学竞技场。药物发现的潜在影响也是巨大的： 诱导致病蛋白质的降解预期是比目前的抑制策略有效得多的治疗。这种方法在治疗癌症和遗传性疾病方面的前景是显而易见的。

DESCRIPTION (provided by applicant): A formidable toolkit exists for manipulating protein expression at the transcriptional level, but the methods for the post-translational modulation of proteins are few and of limited utility. A small molecule that induces degradation of endogenous proteins would clearly be a tremendously useful tool for probing protein function and an exciting approach for chemotherapy. The challenge is to develop technology that is biocompatible and widely applicable. We have serendipitously discovered a moiety that when combined with a recognition element, induces degradation of the target protein. We propose to characterize this phenomenon and develop these novel tools for protein knockdown that will be invaluable in a broad array of biological and pharmaceutical applications. PUBLIC HEALTH RELEVANCE: The ability to manipulate protein levels is invaluable in investigations of biological function, so if successful, this proposal will have an enormous impact in the basic science arena. The potential impact in drug discovery is also substantial: the ability to induce the degradation of pathogenic proteins is expected to be much more effective treatment than current inhibition strategies. The promise of such an approach is readily apparent in the treatment of cancer and hereditary diseases.