title: Expedient synthesis of highly potent antagonists of inhibitor of apoptosis proteins (IAPs) with unique selectivity for ML-IAP.
abstract: A series of novel, potent antagonists of the inhibitor of apoptosis proteins (IAPs) were synthesized in a highly convergent and rapid fashion (≤6 steps) using the Ugi four-component reaction as the key step, thus enabling rapid optimization of binding potency. These IAP antagonists compete with caspases 3, 7, and 9 for inhibition by X chromosome-linked IAP (XIAP) and bind strongly (nanomolar binding constants) to several crucial members of the IAP family of cancer pro-survival proteins to promote apoptosis, with a particularly unique selectivity for melanoma IAP (ML-IAP). Experiments in cell culture revealed powerful cancer cell growth inhibitory activity in multiple (breast, ovarian, and prostate) cell lines with single agent toxicity at low nanomolar levels against SKOV-3 human ovarian carcinoma cells. Administration of the compounds to human foreskin fibroblast cells revealed no general toxicity to normal cells. Furthermore, computational modeling was performed, revealing key contacts between the IAP proteins and antagonists, suggesting a structural basis for the observed potency.
authors: Program in Apoptosis and Cell Death and NCI Designated Cancer Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Mitchell
authors: M
authors: Vamos
authors: Kate
authors: K
authors: Welsh
authors: Darren
authors: D
authors: Finlay
authors: Pooi San
authors: PS
authors: Lee
authors: Peter D
authors: PD
authors: Mace
authors: Scott J
authors: SJ
authors: Snipas
authors: Monica L
authors: ML
authors: Gonzalez
authors: Santhi Reddy
authors: SR
authors: Ganji
authors: Robert J
authors: RJ
authors: Ardecky
authors: Stefan J
authors: SJ
authors: Riedl
authors: Guy S
authors: GS
authors: Salvesen
authors: Kristiina
authors: K
authors: Vuori
authors: John C
authors: JC
authors: Reed
authors: Nicholas D P
authors: ND
authors: Cosford
mesh_terms: D061945:Caspase Inhibitors / Q000494:pharmacology; D015195:Drug Design; D005454:Fluorescence Polarization; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism*; D008958:Models, Molecular
chemical_list: D061945:Caspase Inhibitors; D051034:Inhibitor of Apoptosis Proteins