2-Aminothiazoles (2-ATs) frequently show up as hits in drug discovery assays, but molecules containing this group prove difficult to optimize into lead compounds. The most promiscuous 2-ATs, which have been dubbed PrATs, are particularly problematic when it comes to fragment-based drug discovery, according to Martin J. Scanlon of Monash Institute of Pharmaceutical Sciences, in Australia, and coworkers there and at AstraZeneca, in Macclesfield, England (J. Med. Chem. 2015, DOI: 10.1021/jm501402x). In previous work, at least one 2-AT in Monash’s fragment library showed up as a hit in 14 different screening campaigns that used nuclear magnetic resonance for readout detection. The researchers therefore decided to characterize the binding of all 2-ATs in the fragment library against six protein targets using surface plasmon resonance. In this second set of screens, the same particularly promiscuous member of the class—4-phenylthiazol-2-amine—gave positive results in all six assays. Several other 2-ATs bind at least five of the targets. In addition, no clear structure-activity relationships emerged from analysis of binding of a panel of 2-ATs to the targets. Although a number of known drugs contain a 2-AT group, developing a weakly binding 2-AT fragment into a potent and selective compound appears to be particularly challenging. The researchers advise eliminating them from screening libraries for fragment-based drug discovery.