Discovery of tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists

Abstract Bivalent heterodimeric IAP antagonists that incorporate ( R )- tetrahydroisoquinolinein the P3′ subunit show high affinity for the BIR2 domain and demonstrated potent IAP inhibitory activities in biochemical and cellular assays. Potent in vivo efficacy was observed in a variety of human tumor xenograft models. The bivalent heterodimeric molecule 3 with a P3–P3′ benzamidelinker induced pharmacodynamic markers of apoptosis and was efficacious when administered intravenously at a dose of 1 mg/kg to mice harboring A875 human melanoma tumors. Analog 5 , with a polyamine group incorporated at the P2′ thiovaline side chain exhibited antiproliferative activity against the P-gp expressing HCT116/VM46 cell line.