title: Discovery of aminopiperidine-based Smac mimetics as IAP antagonists.
abstract: A series of structurally unique Smac mimetics that act as antagonists of inhibitor of apoptosis proteins (IAPs) has been discovered. While most previously described Smac mimetics contain the proline ring (or a similar cyclic motif) found in Smac, a key feature of the compounds described herein is that this ring has been removed. Despite this, compounds in this series potently bind to cIAP1 and elicit the expected phenotype of cIAP1 inhibition in cancer cells. Marked selectivity for cIAP1 over XIAP is observed for these compounds, which is attributed to a slight difference in the binding groove between the two proteins and the resulting steric interactions with the inhibitors. XIAP binding can be improved by constraining the inhibitor so that these unfavorable steric interactions are minimized.
authors.affiliation: AstraZeneca R&D Boston, Waltham, MA 02451, United States. edward.hennessy@astrazeneca.com
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hennessy
authors.forename: Jamal C
authors.initials: JC
authors.lastname: Saeh
authors.forename: Li
authors.initials: L
authors.lastname: Sha
authors.forename: Terry
authors.initials: T
authors.lastname: MacIntyre
authors.forename: Haiyun
authors.initials: H
authors.lastname: Wang
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Larsen
authors.forename: Brian M
authors.initials: BM
authors.lastname: Aquila
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Ferguson
authors.forename: Naomi M
authors.initials: NM
authors.lastname: Laing
authors.forename: Charles A
authors.initials: CA
authors.lastname: Omer
mesh_terms: D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D032701:Biomimetics; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D024101:Mitochondrial Proteins / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D010880:Piperidines