Prof. Maurizio Pellecchia and his colleagues at the University of California, Riverside (UCR) have developed novel Lys-covalent IAP inhibitors (Fig. 1) with low nanomolar activity and favorable PK (Fig. 2). When compared to Debio1143 (aka AT-406) and LCL 161, the UCR compounds have improved activity being irreversible. Recently, new irreversible therapeutics in oncology have been developed as potential therapies for a variety of cancer. These irreversible agents present improved pharmacodynamics/ pharmacokinetics (PD/PK) properties over reversible agents, but their design is limited to targets that present a Cys residue within their binding site. UCR deployed a technology consisting of introducing a stable aryl-fluorosulfate electrophile that selectively interacts with Lys residues. UCR Compound 1 (Fig 1) is a potent, pan-IAP, Lys-covalent agent with favorable cell permeability and PK properties and that is likely superior to Debio1143 and LCL161 (Fig. 3). Fig. 1 Chemical composition and covalent docking of compound 1 in the binding pocket of the BIR3 domain of XIAP. Fig. 2 PK studies in mice with compound 1. Fig. 3 TNF sensitization of resistant melanoma cells by AT-406 (aka Debio 1143), LCL161 and the UCR compounds.