Screen for Ras inhibitors

KRAS癌基因的突变发生在大约30%的癌症中，但几乎没有治疗这些癌症的治疗选择。针对KRAS蛋白或其下游效应物的各种策略在过去并不特别成功。在本项目中，我们的目标是采取不同的方法来发现KRAS癌蛋白的抑制剂。我们正在使用高通量化学筛选来鉴定特异性引起KRAS蛋白降解的化合物。重要材料和方法一种基于细胞的测定系统，允许以高通量形式监测小分子对KRAS蛋白水平的影响。FY2012 ACCOMPLISHMENTIn 2011，我们已经证明了HTS形式测定的可行性。2012年，我们进行了试点筛选，并确定了可作为进一步筛选的阳性对照的候选线索。

BACKGROUNDMutations in the KRAS oncogene occur in approximately 30% of cancer yet little therapeutic options exist for the treatment of these cancers. Various strategies to target KRAS protein or its downstream effectors have not been particularly successful in the past.PURPOSEIn this project we aim to take a different approach to discovery inhibitors of the KRAS oncoprotein. We are using high-throughput chemical screening to identify compounds that specifically causes the degradation of KRAS proteins.SIGNIFICANT MATERIALS AND METHODSAn cell-based assay system that allows one to monitor the effect of small molecules on KRAS protein level in a high-throughput format.FY2012 ACCOMPLISHMENTIn 2011 we have demonstrated the feasibility of the assay in HTS format. In 2012 we have conducted a pilot screen and have identified candidate leads that could serve as positive controls for further screens.