Novel molecular strategies for targeting Pin1 to treat cancer

开发治疗癌症的新药是临床和制药研究的重中之重。对于许多癌症，没有有效的药物，或者现有的药物有严重的副作用，对患者的健康产生负面影响。因此，迫切需要开发以更智能的方式起作用的新药。该项目将开发针对重要通讯枢纽蛋白Pin1的尖端药物。Pin1是一种脯氨酸异构酶蛋白，与许多癌症类型密切相关，抑制其活性已被证明是一种有效的治疗策略。一些Pin1小分子抑制剂已经被报道过，但到目前为止还没有产生重大影响。这主要是由于与效力和选择性差有关的问题。此外，Pin1功能的分子基础尚不清楚，这阻碍了其作为药物靶点的成熟。该项目将通过研究最近发现的Pin1的合作双配体抑制、变构配体结合效应以及Pin1磷酸化的后果来解决这些问题。

Developing new drugs to treat cancer is a high priority in clinical and pharmaceutical research. For many cancers there are no effective drugs, or existing drugs have severe side-effects which negatively impact on patient wellbeing. Therefore, there is an urgent need for the development of new medicines that work in smarter ways. This project will develop cutting-edge pharmaceuticals that target an important communication hub protein called Pin1. Pin1 is a prolyl isomerase protein that is heavily implicated in many cancer types and inhibiting its activity has been shown to be an effective therapeutic strategy. A handful of Pin1 small molecule inhibitors have been reported, but so far none have made a significant impact. This is largely due to problems associated with poor potency and selectivity. Furthermore, the molecular basis for Pin1 function is poorly understood which hampers its maturation as a drug target. This project will address these issues by investigating recently discovered cooperative dual ligand inhibition of Pin1, allosteric ligand binding effects, and consequences of Pin1 phosphorylation.