Co- and post-translational protein processing is important to ensure the maturation to functional proteins. MetAP-2 proteolytically removes the amino-terminal methionine from nascent proteins, and inhibition of its activity has been shown to block angiogenesis and tumor growth, suggesting that small-molecule inhibitors of MetAP-2 may be promising options for the treatment of cancer. This talk describes how persistence and serendipity helped to identify a previously unknown MetAP-2 inhibitory scaffold. The biochemical activity of more conventional, purine base compounds did not translate to cellular activity. Thorough analysis of HTS screening results led to the identification of chiral tartronic diamide hits. Structure-based hit-to-lead optimization is out-lined, including different synthetic strategies for most efficient access to improved derivatives as well as asymmetric approaches. The initial lead compound suffered from enterohepatic circulation, preventing further development. Binding kinetics were investigated by fluorescence cross correlation spectroscopy and residence time on the target protein was one important characterization criterion. Adjustment of H-bond donor/acceptor count and multiparameter analysis of the compound properties led to the nomination of the clinical development compound M8891, which impedes the growth of primary endothelial cells, shows dose-dependent biomarker modulation and antitumoral activity in mouse xenograft models.