14 research outputs found
Benzazepinones and Benzoxazepinones as Antagonists of Inhibitor of Apoptosis Proteins (IAPs) Selective for the Second Baculovirus IAP Repeat (BIR2) Domain
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 <b>40</b>, 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