Inhibitors of apoptosis (IAP) protein family

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Inhibitors of apoptosis (IAP) protein family

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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The Inhibitors of apoptosis (IAP) are a family of functionally and structurally related proteins. The human family has eight members: NAIP (BIRC1), BIRC2 (cIAPl), BIRC3 (cIAP2), XIAP (BIRC4), BIRC5 (survivin), BIRC6 (apollon), BIRC7 (livin) and BIRC8. All members of the family contain 1-3 copies of a 70-80 amino acid motif known as BIR (baculovirus IAP repeat). The IAPs have garnered interest as drug targets with antineoplastic [1,4,16] and immunomodulatory [7] potential. Small molecule, antagonistic, peptide mimetics have been described [4,9-10,14].

Targets

2794

NLR family apoptosis inhibitory protein Show summary »« Hide summary More detailed page go icon to follow link

Target Id	2793
Nomenclature	NLR family apoptosis inhibitory protein
Previous and unofficial names	baculoviral IAP repeat-containing 1 \| BIRC1 \| Birc1a \| Birc1b \| neuronal apoptosis inhibitory protein \| NLRB1 \| NLR family, apoptosis inhibitory protein \| NLR family, apoptosis inhibitory protein 2 \| NLR family, BIR domain containing 1 \| psiNAIP
Genes	NAIP (Hs)
Ensembl ID	ENSG00000249437 (Hs)
UniProtKB AC	Q13075 (Hs)
Comment	NAIP has 7 reported murine orthologues of which NAIP1, NAIP2, NAIP5 and NAIP6 are functional. Co-operates with NLRC4 to form an inflammasome.

baculoviral IAP repeat containing 2 Show summary »« Hide summary More detailed page go icon to follow link

baculoviral IAP repeat containing 3 Show summary »« Hide summary More detailed page go icon to follow link

X-linked inhibitor of apoptosis Show summary »« Hide summary More detailed page go icon to follow link

Target Id

2790

Nomenclature

X-linked inhibitor of apoptosis

Previous and unofficial names

hILP | API3 | baculoviral IAP repeat-containing 4 | BIRC4 | X-linked inhibitor of apoptosis, E3 ubiquitin protein ligase

Genes

XIAP (Hs), Xiap (Mm), Xiap (Rn)

Ensembl ID

ENSG00000101966 (Hs), ENSMUSG00000025860 (Mm), ENSRNOG00000006967 (Rn)

UniProtKB AC

P98170 (Hs), Q60989 (Mm), Q9R0I6 (Rn)

Sub/family-selective inhibitors

LCL161 pIC₅₀ 7.5 [6]

Selective inhibitors

BV-6 pK_d 8.9 [18]

baculoviral IAP repeat containing 5 Show summary »« Hide summary

Target Id

2795

Nomenclature

baculoviral IAP repeat containing 5

Previous and unofficial names

survivin | API4 (apoptosis inhibitor 4) | EPR-1

Genes

BIRC5 (Hs), Birc5 (Mm), Birc5 (Rn)

Ensembl ID

ENSG00000089685 (Hs), ENSMUSG00000017716 (Mm), ENSRNOG00000050819 (Rn)

UniProtKB AC

O15392 (Hs), O70201 (Mm), Q9JHY7 (Rn)

Inhibitors

compound III [PMID: 24080463] pIC₅₀ 4.6 [11]

Comment

Survivin was proposed as an oncology drug target [3,5]. Antisense oligonucleotides that disrupt survivin expression have been investigated for anti-tumour potential [2,12-13,15,17,19], but to date none have reached clinical use. Small-molecule survivin inhibitors have also been evaluated [11], as has modulating molecular targets which have an indirect action on survivin expression [20].

baculoviral IAP repeat containing 6 Show summary »« Hide summary

baculoviral IAP repeat containing 7 Show summary »« Hide summary

Target Id

2794

Nomenclature

baculoviral IAP repeat containing 7

Previous and unofficial names

KIAP (kidney inhibitor of apoptosis protein) | livin | ML-IAP (melanoma inhibitor of apoptosis protein) | baculoviral IAP repeat-containing 7 (livin)

Genes

BIRC7 (Hs), Birc7 (Mm), Birc7 (Rn)

Ensembl ID

ENSG00000101197 (Hs), ENSMUSG00000038840 (Mm), ENSRNOG00000043311 (Rn)

UniProtKB AC

Q96CA5 (Hs), A2AWP0 (Mm)

Sub/family-selective antagonists

GDC-0152 pK_i 7.8 [8]

baculoviral IAP repeat containing 8 Show summary »« Hide summary

Target Id	2797
Nomenclature	baculoviral IAP repeat containing 8
Previous and unofficial names	ILP-2 (IAP-like protein 2) \| inhibitor of apoptosis-like protein 2
Genes	BIRC8 (Hs)
Ensembl ID	ENSG00000163098 (Hs)
UniProtKB AC	Q96P09 (Hs)

References

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1. Bai L, Smith DC, Wang S. (2014) Small-molecule SMAC mimetics as new cancer therapeutics. Pharmacol Ther, 144 (1): 82-95. [PMID:24841289]

2. Callies S, André V, Patel B, Waters D, Francis P, Burgess M, Lahn M. (2011) Integrated analysis of preclinical data to support the design of the first in man study of LY2181308, a second generation antisense oligonucleotide. Br J Clin Pharmacol, 71 (3): 416-28. [PMID:21284701]

3. Church DN, Talbot DC. (2012) Survivin in solid tumors: rationale for development of inhibitors. Curr Oncol Rep, 14 (2): 120-8. [PMID:22234703]

4. Cong H, Xu L, Wu Y, Qu Z, Bian T, Zhang W, Xing C, Zhuang C. (2019) Inhibitor of Apoptosis Protein (IAP) Antagonists in Anticancer Agent Discovery: Current Status and Perspectives. J Med Chem, 62 (12): 5750-5772. [PMID:30676015]

5. Coumar MS, Tsai FY, Kanwar JR, Sarvagalla S, Cheung CH. (2013) Treat cancers by targeting survivin: just a dream or future reality?. Cancer Treat Rev, 39 (7): 802-11. [PMID:23453862]

6. 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]

7. Estornes Y, Bertrand MJ. (2015) IAPs, regulators of innate immunity and inflammation. Semin Cell Dev Biol, 39: 106-14. [PMID:24718315]

8. 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]

9. Hassan M, Watari H, AbuAlmaaty A, Ohba Y, Sakuragi N. (2014) Apoptosis and molecular targeting therapy in cancer. Biomed Res Int, 2014: 150845. [PMID:25013758]

10. 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]

11. Ho SS, Go ML. (2013) Restraining the flexibility of the central linker in terameprocol results in constrained analogs with improved growth inhibitory activity. Bioorg Med Chem Lett, 23 (22): 6127-33. [PMID:24080463]

12. Lamers F, van der Ploeg I, Schild L, Ebus ME, Koster J, Hansen BR, Koch T, Versteeg R, Caron HN, Molenaar JJ. (2011) Knockdown of survivin (BIRC5) causes apoptosis in neuroblastoma via mitotic catastrophe. Endocr Relat Cancer, 18 (6): 657-68. [PMID:21859926]

13. Natale R, Blackhall F, Kowalski D, Ramlau R, Bepler G, Grossi F, Lerchenmüller C, Pinder-Schenck M, Mezger J, Danson S et al.. (2014) Evaluation of antitumor activity using change in tumor size of the survivin antisense oligonucleotide LY2181308 in combination with docetaxel for second-line treatment of patients with non-small-cell lung cancer: a randomized open-label phase II study. J Thorac Oncol, 9 (11): 1704-8. [PMID:25436803]

14. 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]

15. Raetz EA, Morrison D, Romanos-Sirakis E, Gaynon P, Sposto R, Bhojwani D, Bostrom BC, Brown P, Eckroth E, Cassar J et al.. (2014) A phase I study of EZN-3042, a novel survivin messenger ribonucleic acid (mRNA) antagonist, administered in combination with chemotherapy in children with relapsed acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium. J Pediatr Hematol Oncol, 36 (6): 458-63. [PMID:24276047]

16. Saleem M, Qadir MI, Perveen N, Ahmad B, Saleem U, Irshad T, Ahmad B. (2013) Inhibitors of apoptotic proteins: new targets for anticancer therapy. Chem Biol Drug Des, 82 (3): 243-51. [PMID:23790005]

17. Sapra P, Wang M, Bandaru R, Zhao H, Greenberger LM, Horak ID. (2010) Down-modulation of survivin expression and inhibition of tumor growth in vivo by EZN-3042, a locked nucleic acid antisense oligonucleotide. Nucleosides Nucleotides Nucleic Acids, 29 (2): 97-112. [PMID:20391197]

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]

19. Wiechno P, Somer BG, Mellado B, Chłosta PL, Cervera Grau JM, Castellano D, Reuter C, Stöckle M, Kamradt J, Pikiel J et al.. (2014) A randomised phase 2 study combining LY2181308 sodium (survivin antisense oligonucleotide) with first-line docetaxel/prednisone in patients with castration-resistant prostate cancer. Eur Urol, 65 (3): 516-20. [PMID:24246407]

20. Yuan J, Liu Z, Dong Y, Gao F, Xia X, Wang P, Luo Y, Zhang Z, Yan D, Zhang W. (2023) Pioneering 4,11-Dioxo-4,11-dihydro-1H-anthra[2,3-d]imidazol-3-ium Compounds as Promising Survivin Inhibitors by Targeting ILF3/NF110 for Cancer Therapy. J Med Chem, 66 (24): 16843-16868. [PMID:38079530]

How to cite this family page

Database page citation:

Inhibitors of apoptosis (IAP) protein family. Accessed on 16/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=889.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Buneman OP, Faccenda E, Harding SD, Spedding M, Cidlowski JA, Fabbro D, Davenport AP, Striessnig J, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Introduction and Other Protein Targets. Br J Pharmacol. 180 Suppl 2:S1-22.