Expedient Synthesis of
Highly Potent Antagonists of
Inhibitor of Apoptosis Proteins (IAPs) with Unique Selectivity for
ML-IAP
- Publication date
- Publisher
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