Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer.
Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. thorsten.oost@abbott.com
Thorsten K
TK
Oost
Chaohong
C
Sun
Robert C
RC
Armstrong
Ali-Samer
AS
Al-Assaad
Stephen F
SF
Betz
Thomas L
TL
Deckwerth
Hong
H
Ding
Steven W
SW
Elmore
Robert P
RP
Meadows
Edward T
ET
Olejniczak
Andrew
A
Oleksijew
Tilman
T
Oltersdorf
Saul H
SH
Rosenberg
Alexander R
AR
Shoemaker
Kevin J
KJ
Tomaselli
Hua
H
Zou
Stephen W
SW
Fesik
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002352:Carrier Proteins / Q000737:chemistry* / Q000627:therapeutic use; D020169:Caspases / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D051379:Mice; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000737:chemistry / Q000627:therapeutic use*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D051636:X-Linked Inhibitor of Apoptosis Protein
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C412403:DIABLO protein, human; C499605:Diablo protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D020169:Caspases