Inhibitor mediated protein degradation

描述（由申请人提供）：存在一个强大的工具箱，用于在转录水平上操纵蛋白质表达，但是用于蛋白质翻译后调节的方法很少，而且实用性有限。一种诱导内源性蛋白质降解的小分子显然将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。面临的挑战是开发具有生物相容性和广泛应用的技术。我们偶然发现了一个片段，当它与识别元件结合时，会导致目标蛋白的降解。我们建议描述这一现象，并开发这些新的蛋白质敲除工具，这将在广泛的生物和制药应用中具有不可估量的价值。

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.