STRUCTURE OF UROKINASE RECEPTOR IN COMPLEX TO ITS INHIBITORS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 肿瘤转移引起的并发症是癌症死亡的主要原因。尿激酶受体(UPAR)被广泛认为是治疗肿瘤转移的靶点。抑制uPAR的表达在不同程度上逆转了肿瘤的侵袭和抑制了肿瘤的转移。尿激酶受体是细胞周围纤溶酶原激活的关键，在肿瘤相关间质和某些肿瘤中过度表达。通过一些方法下调uPAR的表达，如抗基因技术，已被证明在不同程度上逆转了肿瘤的侵袭和抑制了肿瘤的转移。尽管经过十多年的研究发现了许多类型的uPAR拮抗剂，但没有一种被转移到临床前阶段。我们通过一系列的结构研究确定了uPAR抑制剂在药物开发中面临的主要挑战。我们确定了人和鼠的uPAR配体复合体的一系列晶体结构。这些结构揭示了uPAR表面有一个很深的配体结合口袋(14°)，这表明有可能使用小分子抑制剂来干预这种相互作用。我们的研究还表明，人类和小鼠的uPAR具有共同的配基识别区域，因此有可能开发人和小鼠uPAR的抑制剂。我们已经开发了识别uPAR的小分子抑制剂的策略。对uPAR-抑制剂复合体的结构研究是我们战略的组成部分。本研究确定的抑制物不仅不能用于基础研究其对细胞迁移机制的影响，而且还可能导致发现治疗肿瘤转移的疗法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Complications resulted from tumor metastasis are the major causes of cancer death. Urokinase receptor (uPAR) is widely accepted as a target for treatment of tumor metastasis. Suppression of uPAR expression has shown to reverse tumor invasion and inhibit tumor metastasis on several cancers to various extents. Urokinase receptor is critical for pericellular plasminogen activation and is over-expressed in the tumor-associated stroma and in some tumors. Down-regulation of uPAR expression by several approaches, e.g. anti-gene techniques, has shown to reverse tumor invasion and inhibit tumor metastasis on several cancers to various extents. Despite that many types of uPAR antagonists being identified through over a decade of studies, none of them was moved to preclinical stage. We have identified the major challenges for the drug development of uPAR inhibitors through a series of structural studies.We determined a series of crystal structures of human and murine uPAR-ligand complexes. These structures reveals a deep ligand binding pocket (14 ¿) on uPAR surface, suggesting the possibility to intervene with this interaction using small molecular inhibitors. Our studies also show that human and murine uPAR share a common region for ligand recognition, and thus possibility to develop inhibitors for both human and murine uPAR.We have developed strategies to identify small molecular inhibitors of uPAR. Structural studies of uPAR-inhibitor complexes are an integral part of our stragegies. The inhibitors identified from this study will not be useful for basic research on their effects on cell migration mechanism, but may also lead to the discovery of therapeutics for the treatment of tumor metastasis.