Integrated phenotypic screening and activity-based protein profiling to reveal potential therapy targets of pancreatic cancer.

Pancreatic cancer has been defined as one of the most complex and challenging cancers to treat, but very few valid therapeutic targets have been identified to date. To address this issue, a 61-compound library was readily created by Ugi reaction followed by phenotypic screening, leading to the discovery of two most potent inhibitors, P21 and P26, which significantly impair BxPC-3 pancreatic cancer cell survival. A series of interacting protein hits, such as GSTO1, FAM213A, RAB6A/6B/39A and USMG5, were subsequently identified by quantitative chemoproteomics studies. The main cellular target, GSTO1, was further validated as a novel pancreatic cancer therapeutic target.