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X-linked inhibitor of apoptosis

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2790

Nomenclature: X-linked inhibitor of apoptosis

Family: Inhibitors of apoptosis (IAP) protein family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 497 Xq25 XIAP X-linked inhibitor of apoptosis
Mouse - 496 X A4 Xiap X-linked inhibitor of apoptosis
Rat - 496 Xq35 Xiap X-linked inhibitor of apoptosis
Previous and Unofficial Names Click here for help
hILP | API3 | baculoviral IAP repeat-containing 4 | BIRC4 | X-linked inhibitor of apoptosis, E3 ubiquitin protein ligase
Database Links Click here for help
Alphafold P98170 (Hs), Q60989 (Mm), Q9R0I6 (Rn)
ChEMBL Target CHEMBL4198 (Hs)
Ensembl Gene ENSG00000101966 (Hs), ENSMUSG00000025860 (Mm), ENSRNOG00000006967 (Rn)
Entrez Gene 331 (Hs), 11798 (Mm), 63879 (Rn)
Human Protein Atlas ENSG00000101966 (Hs)
KEGG Gene hsa:331 (Hs), mmu:11798 (Mm), rno:63879 (Rn)
OMIM 300079 (Hs)
Pharos P98170 (Hs)
RefSeq Nucleotide NM_001167 (Hs), NM_001301639 (Mm), NM_022231 (Rn)
RefSeq Protein NP_001158 (Hs), NP_001288568 (Mm), NP_071567 (Rn)
UniProtKB P98170 (Hs), Q60989 (Mm), Q9R0I6 (Rn)
Wikipedia XIAP (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the complex of XIAP-BIR2 and caspase 3
PDB Id:  1I3O
Resolution:  2.7Å
Species:  Human
References:  16
Image of receptor 3D structure from RCSB PDB
Description:  Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Compound 4
PDB Id:  5C3K
Ligand:  compound 4 [PMID: 26218264]
Resolution:  2.02Å
Species:  Human
References:  4

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
BV-6 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.9 pKd 18
⤷ pKd 8.9 (Kd 1.3x10-9 M) [18]
Description: Assayed using expressed XIAP BIR2-BIR3 domain construct
SM-122 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.6 pKi 15
⤷ pKi 7.6 (Ki 2.6x10-8 M) [15]
tolinapant Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.6 pIC50 12
⤷ pIC50 8.6 (IC50 2.8x10-9 M) [12]
Description: Determined in a cellular XIAP-caspase 9 immunoprecipitation assay
LCL161 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.5 pIC50 7
⤷ pIC50 7.5 (IC50 3x10-8 M) [7]
Description: Assay uses recombinantly expressed BIR3 domain of XIAP
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
birinapant Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 7.3 pKd 1
⤷ pKd 7.3 (Kd 4.5x10-8 M) [1]
SM-337 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Antagonist 7.6 pKi 15
⤷ pKi 7.6 (Ki 2.6x10-8 M) [15]
Description: Fluorescence polarization assay using hXIAP BIR3 domain (residues 241-356)
GDC-0152 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Antagonist 7.6 pKi 9
⤷ pKi 7.6 (Ki 2.8x10-8 M) [9]
Description: BIR3 domain of hXIAP
xevinapant Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.2 pKi 3
⤷ pKi 7.2 (Ki 6.64x10-8 M) [3]
Description: Competitive inhibition of human XIAP BIR3 domain expressed in Escherichia coli.
AZD5582 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Antagonist 7.8 pIC50 11
⤷ pIC50 7.8 (IC50 1.5x10-8 M) [11]
Antagonist Comments
AZD5582 is a peptide mimetic. It consists of a dimeric structure, with sequences based on the AVPI motif of DIABLO (aka Smac; Q9NR28). DIABLO is a peptide of mitochondrial origin and is an endogenous pro-apoptotic antagonist of IAP protein function.
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 20 [PMID: 34432979] Small molecule or natural product Click here for species-specific activity table Hs Binding 7.4 pIC50 13
⤷ pIC50 7.4 (IC50 3.98x10-8 M) [13]
Description: Binding to the BIR2 domain of hXIAP determined using a fluorescence polarisation assay.
Immunopharmacology Comments
Mouse experiments suggest that XIAP regulates innate immune responses (to Listeria monocytogenes infection) by potentiating synergy between Toll-like receptors (TLRs) and NOD-like receptors (NLRs) through activation of JNK- and NF-κB-dependent signaling [2].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Immune regulation
Immuno Process:  Cellular signalling
Physiological Consequences of Altering Gene Expression Click here for help
Xiap null mice have an impaired innate immune control of Listeria monocytogenes infection.
Species:  Mouse
Tissue: 
Technique: 
References:  2
Xiap null mice develop normally and have no overt defect in apoptotic function. They do however, upregulate expression of the related IAPs, cIAP1 and cIAP2, potentially as a compensatory mechanism in the absence of Xiap protein..
Species:  Mouse
Tissue: 
Technique:  Homologous gene targeting
References:  10
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Lymphoproliferative syndrome, X-linked, 2; XLP2
Synonyms: Duncan disease
Duncan's syndrome
Lymphoproliferative disease [Disease Ontology: DOID:619]
X-linked lymphoproliferative disease [Orphanet: ORPHA2442]
Disease Ontology: DOID:619
OMIM: 300635
Orphanet: ORPHA2442
General Comments
XIAP binds directly to the key apoptotic proteases, caspase 3, 7 and 9 [6] and may be the only bona fide caspase inhibitor in this protein family [8]. Caspases 3 and 7 are executioner caspases involved in the effector arm of apoptosis [14]. Binding interaction occurs between the BIR2 (second baculovirus IAP repeat) domain of XIAP and the active-site substrate groove of these caspases [8]. The interaction with caspase 9 occurs via the third BIR domain [5,17].

References

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1. Allensworth JL, Sauer SJ, Lyerly HK, Morse MA, Devi GR. (2013) Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism. Breast Cancer Res Treat, 137 (2): 359-71. [PMID:23225169]

2. Bauler LD, Duckett CS, O'Riordan MX. (2008) XIAP regulates cytosol-specific innate immunity to Listeria infection. PLoS Pathog, 4 (8): e1000142. [PMID:18769721]

3. Cai Q, Sun H, Peng Y, Lu J, Nikolovska-Coleska Z, McEachern D, Liu L, Qiu S, Yang CY, Miller R et al.. (2011) A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment. J Med Chem, 54 (8): 2714-26. [PMID:21443232]

4. Chessari G, Buck IM, Day JE, Day PJ, Iqbal A, Johnson CN, Lewis EJ, Martins V, Miller D, Reader M et al.. (2015) Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP. J Med Chem, 58 (16): 6574-88. [PMID:26218264]

5. Deveraux QL, Leo E, Stennicke HR, Welsh K, Salvesen GS, Reed JC. (1999) Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases. EMBO J, 18 (19): 5242-51. [PMID:10508158]

6. Deveraux QL, Reed JC. (1999) IAP family proteins--suppressors of apoptosis. Genes Dev, 13 (3): 239-52. [PMID:9990849]

7. Donnell AF, Michoud C, Rupert KC, Han X, Aguilar D, Frank KB, Fretland AJ, Gao L, Goggin B, Hogg JH et al.. (2013) Benzazepinones and benzoxazepinones as antagonists of inhibitor of apoptosis proteins (IAPs) selective for the second baculovirus IAP repeat (BIR2) domain. J Med Chem, 56 (20): 7772-87. [PMID:24083782]

8. Eckelman BP, Salvesen GS, Scott FL. (2006) Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep, 7 (10): 988-94. [PMID:17016456]

9. Flygare JA, Beresini M, Budha N, Chan H, Chan IT, Cheeti S, Cohen F, Deshayes K, Doerner K, Eckhardt SG et al.. (2012) Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152). J Med Chem, 55 (9): 4101-13. [PMID:22413863]

10. Harlin H, Reffey SB, Duckett CS, Lindsten T, Thompson CB. (2001) Characterization of XIAP-deficient mice. Mol Cell Biol, 21 (10): 3604-8. [PMID:11313486]

11. Hennessy EJ, Adam A, Aquila BM, Castriotta LM, Cook D, Hattersley M, Hird AW, Huntington C, Kamhi VM, Laing NM et al.. (2013) Discovery of a novel class of dimeric Smac mimetics as potent IAP antagonists resulting in a clinical candidate for the treatment of cancer (AZD5582). J Med Chem, 56 (24): 9897-919. [PMID:24320998]

12. Johnson CN, Ahn JS, Buck IM, Chiarparin E, Day JEH, Hopkins A, Howard S, Lewis EJ, Martins V, Millemaggi A et al.. (2018) A Fragment-Derived Clinical Candidate for Antagonism of X-Linked and Cellular Inhibitor of Apoptosis Proteins: 1-(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2 H,3 H-pyrrolo[3,2- b]pyridin-1-yl)-2-[(2 R,5 R)-5-methyl-2-([(3R)-3-methylmorpholin-4-yl]methyl)piperazin-1-yl]ethan-1-one (ASTX660). J Med Chem, 61 (16): 7314-7329. [PMID:30091600]

13. Miah AH, Smith IED, Rackham M, Mares A, Thawani AR, Nagilla R, Haile PA, Votta BJ, Gordon LJ, Watt G et al.. (2021) Optimization of a Series of RIPK2 PROTACs. J Med Chem, 64 (17): 12978-13003. [PMID:34432979]

14. Nicholson DW. (1999) Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ, 6 (11): 1028-42. [PMID:10578171]

15. Peng Y, Sun H, Nikolovska-Coleska Z, Qiu S, Yang CY, Lu J, Cai Q, Yi H, Kang S, Yang D et al.. (2008) Potent, orally bioavailable diazabicyclic small-molecule mimetics of second mitochondria-derived activator of caspases. J Med Chem, 51 (24): 8158-62. [PMID:19049347]

16. Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW, Liddington RC, Salvesen GS. (2001) Structural basis for the inhibition of caspase-3 by XIAP. Cell, 104 (5): 791-800. [PMID:11257232]

17. Sun C, Cai M, Meadows RP, Xu N, Gunasekera AH, Herrmann J, Wu JC, Fesik SW. (2000) NMR structure and mutagenesis of the third Bir domain of the inhibitor of apoptosis protein XIAP. J Biol Chem, 275 (43): 33777-81. [PMID:10934209]

18. Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, Zobel K, Dynek JN, Elliott LO, Wallweber HJ et al.. (2007) IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell, 131 (4): 669-81. [PMID:18022362]

How to cite this page

Inhibitors of apoptosis (IAP) protein family: X-linked inhibitor of apoptosis. Last modified on 05/06/2023. Accessed on 22/01/2025. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2790.