Characterization of a Potent and Orally Bioavailable Lys-Covalent Inhibitor of Apoptosis Protein (IAP) Antagonist

We have recently reported on the use of aryl-fluorosulfatesindesigning water- and plasma-stable agents that covalently target Lys,Tyr, or His residues in the BIR3 domain of the inhibitor of the apoptosisprotein (IAP) family. Here, we report further structural, cellular,and pharmacological characterizations of this agent, including thehigh-resolution structure of the complex between the Lys-covalentagent and its target, the BIR3 domain of X-linked IAP (XIAP). We alsocompared the cellular efficacy of the agent in two-dimensional (2D)and three-dimensional (3D) cell cultures, side by side with the clinicalcandidate reversible IAP inhibitor LCL161. Finally, in vivo pharmacokinetic studies indicated that the agent was long-livedand orally bioavailable. Collectively our data further corroboratethat aryl-fluorosulfates, when incorporated correctly in a ligand,can result in Lys-covalent agents with pharmacodynamic and pharmacokineticproperties that warrant their use in the design of pharmacologicalprobes or even therapeutics.