Small-molecule pan-IAP antagonists: a patent review.
BACKGROUND
The inhibitor of apoptosis (IAP) proteins are critical regulators of cancer cell survival that have become important targets for therapeutic intervention in human malignancies. One strategy for targeting IAP proteins involves agents that mimic the amino terminus of the endogenous IAP protein antagonist second mitochondria-derived activator of caspases (Smac)/direct IAP-binding protein with low pI (DIABLO) and thus block critical IAP protein interactions.


METHODS
This review of the IAP antagonist patent literature covers the period from 2000 to mid-2009. Over 50 patents and patent applications pertaining to IAP antagonists have been published over the past 10 years. In the case of several filings, only the original source is reviewed in this analysis.


RESULTS
Readers will gain an overview of IAP protein antagonist scaffolds, with representative examples including monovalent and bivalent Smac mimetics, and an understanding of their structure-activity relationships.


CONCLUSIONS
The feasibility of disrupting IAP protein interactions with pro-apoptotic proteins using monovalent and bivalent Smac-derived peptidomimetic compounds has been broadly established. Four such compounds have entered or been approved to enter human clinical trials, which will hopefully allow the utility of this potential therapeutic approach to be evaluated in cancer patients.
Flygare
John A
JA
Genentech, Inc., Department of Medicinal Chemistry, 1 DNA Way, South San Francisco, CA 94080, USA.
Fairbrother
Wayne J
WJ
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010330:Patents as Topic; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D009842:Oligopeptides; C532637:SMAC peptide