Benzazepinones and Benzoxazepinones as Antagonists of Inhibitor of Apoptosis Proteins (IAPs) Selective for the Second Baculovirus IAP Repeat (BIR2) Domain

Abstract

XIAP is a key regulator of apoptosis, and its overexpression in cancer cells may contribute to their survival. The antiapoptotic function of XIAP derives from its BIR domains, which bind to and inhibit pro-apoptotic caspases. Most known IAP inhibitors are selective for the BIR3 domain and bind to cIAP1 and cIAP2 as well as XIAP. Pathways activated upon cIAP binding contribute to the function of these compounds. Inhibitors selective for XIAP should exert pro-apoptotic effects through competition with the terminal caspases. This paper details our synthetic explorations of a novel XIAP BIR2-selective benzazepinone screening hit with a focus on increasing BIR2 potency and overcoming high in vivo clearance. These efforts led to the discovery of benzoxazepinone 40, a potent BIR2-selective inhibitor with good in vivo pharmacokinetic properties which potentiates apoptotic signaling in a manner mechanistically distinct from that of known pan-IAP inhibitors.

Small molecules, big targets: drug discovery faces the protein–protein interaction challenge

“…The compounds that scored best were then synthesised and tested for the ability to abrogate the protein interaction. Although the compounds were only modestly potent 135,136 Such inhibitors are anticipated to have different pharmacodynamics profiles to the less selective compounds.…”

Targeting the BIR Domains of Inhibitor of Apoptosis (IAP) Proteins in Cancer Treatment

“…As a result, bulky and flat chemical groups (like phenylhydrazine or 1-naphthyl moieties) appear to be better suited for the shallow CBC, enhancing both BIR2 affinity and selectivity [ 95 ]. In the last years, through a structure-based approach, novel XIAP-directed compounds were developed [ 96 , 97 ] by exploiting the increased selectivity for the BIR2 domain of XIAP compared to the BIR3 of XIAP and cIAP1. These compounds were shown to promote apoptosis without inducing cIAP1 degradation [ 98 ].…”

A potential role of X-linked inhibitor of apoptosis protein in mitochondrial membrane permeabilization and its implication in cancer therapy

“…Recently, another study optimized XIAP-BIR2-selective benzazepinone[s8] screening and identified benzoxazepinone 40, a more potent BIR2-selective inhibitor with better in vivo pharmacokinetic properties. Benzoxazepinone 40 enhances mechanistically distinct apoptotic signaling compared to pan-IAP inhibitors [112]. Because Smac binds with XIAP leading to the induction of apoptotic cell death [44], various Smac mimetics have been developed to inhibit prosurvival function of XIAP, which could have significance in cancer therapy [113–118].…”