1. University of Cambridge, UK
2. University of Sunderland, UK

Abstract

Integrins are unusual signalling proteins that function to signal both from the extracellular environment into the cell, but also from the cytoplasm to the external of the cell. The intracellular signalling cascades associated with integrin activation focus on protein kinase activities, such as focal adhesion kinase and Src. Based on this association between extracellular signals and intracellular protein kinase activity, we have chosen to include integrins in the 'Catalytic receptors' section of the database until more stringent criteria from NC-IUPHAR allows precise definition of their classification.

Integrins are heterodimeric entities, composed of α and β subunits, each 1TM proteins, which bind components of the extracellular matrix or counter-receptors expressed on other cells. One class of integrin contains an inserted domain (I) in its α subunit, and if present (in α1, α2, α10, α11, αD, αE, αL, αM and αX), this I domain contains the ligand binding site. All β subunits possess a similar I-like domain, which has the capacity to bind ligand, often recognising the RGD motif. The presence of an α subunit I domain precludes ligand binding through the β subunit. Integrins provide a link between ligand and the actin cytoskeleton (through typically short intracellular domains). Integrins bind several divalent cations, including a Mg²⁺ ion in the I or I-like domain that is essential for ligand binding. Other cation binding sites may regulate integrin activity or stabilise the 3D structure. Integrins regulate the activity of particular protein kinases, including focal adhesion kinase and integrin-linked kinase. Cellular activation regulates integrin ligand affinity via inside-out signalling and ligand binding to integrins can regulate cellular activity via outside-in signalling.

Several drugs that target integrins are in clinical use including: (1) abciximab (αIIbβ3) for short term prevention of coronary thrombosis, (2) vedolizumab (α4β7) to reduce gastrointestinal inflammation, and (3) natalizumab (α4β1) in some cases of severe multiple sclerosis.

Contents

GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts. For further details see [7].

Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version. If you need to consult the cited version, rather than the most recent version, please contact the GtoPdb curators.

Database links

References

1. Anderson NA, Campos S, Butler S, Copley RCB, Duncan I, Harrison S, Le J, Maghames R, Pastor-Garcia A and Pritchard JM et al.. (2019) Discovery of an Orally Bioavailable Pan αv Integrin Inhibitor for Idiopathic Pulmonary Fibrosis. J Med Chem 62: 8796-8808 [PMID:31497959]
2. Barrett TN, Taylor JA, Barker D, Procopiou PA, Thompson JDF, Barrett J, Le J, Lynn SM, Pogany P and Pratley C et al.. (2019) Profile of a Highly Selective Quaternized Pyrrolidine Betaine α_vβ₆ Integrin Inhibitor-(3S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((1S and 1R,3R)-1-methyl-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-ium-1-yl)butanoate Synthesized by Stereoselective Methylation. J Med Chem 62: 7543-7556 [PMID:31381331]
3. Bhaskar V, Fox M, Breinberg D, Wong MH, Wales PE, Rhodes S, DuBridge RB and Ramakrishnan V. (2008) Volociximab, a chimeric integrin alpha5beta1 antibody, inhibits the growth of VX2 tumors in rabbits. Invest New Drugs 26: 7-12 [PMID:17786386]
4. Bhaskar V, Zhang D, Fox M, Seto P, Wong MH, Wales PE, Powers D, Chao DT, Dubridge RB and Ramakrishnan V. (2007) A function blocking anti-mouse integrin alpha5beta1 antibody inhibits angiogenesis and impedes tumor growth in vivo. J Transl Med 5: 61 [PMID:18042290]
5. Boehringer Ingelheim. LFA-1 (lymphocyte function-associated antigen-1) antagonist | BI-1950 https://www.opnme.com/molecules/lfa-1-bi-1950. Accessed on 28/11/2017.
6. Breitenstein W, Huerzeler M, Kelly T, Mancuso R, Schneider G and Weitz-Schmidt G. (2015) Small molecule lfa-1 inhibitors Patent number: WO2015189265. Assignee: Allocyte Pharmaceuticals Ag. Priority date: 12/06/2014. Publication date: 17/12/2015.
7. Buneman P, Christie G, Davies JA, Dimitrellou R, Harding SD, Pawson AJ, Sharman JL and Wu Y. (2020) Why data citation isn't working, and what to do about it Database 2020 [PMID:32367113]
8. Coller BS and Knight DM. (1999) Method of antithrombotic therapy using anti-GPIIb/IIIa antibodies or fragments thereof, including c7E3. Patent number: US5976532. Assignee: Centocor, Inc.. Priority date: 18/05/1988. Publication date: 02/11/1999.
9. Decaris ML, Schaub JR, Chen C, Cha J, Lee GG, Rexhepaj M, Ho SS, Rao V, Marlow MM and Kotak P et al.. (2021) Dual inhibition of α_vβ₆ and α_vβ₁ reduces fibrogenesis in lung tissue explants from patients with IPF. Respir Res 22: 265 [PMID:34666752]
10. Derkach DN, Wadekar SA, Perkins KB, Rousseau E, Dreiza CM, Cheung-Flynn J, Ramos HC, Ugarova TP and Sheller MR. (2010) RGD-dependent binding of TP508 to integrin alphavbeta3 mediates cell adhesion and induction of nitric oxide. Thromb Haemost 104: 172-82 [PMID:20508901]
11. Dinauer MC. (2019) Inflammatory consequences of inherited disorders affecting neutrophil function. Blood 133: 2130-2139 [PMID:30898864]
12. Eldred CD, Evans B, Hindley S, Judkins BD, Kelly HA, Kitchin J, Lumley P, Porter B, Ross BC and Smith KJ et al.. (1994) Orally active non-peptide fibrinogen receptor (GpIIb/IIIa) antagonists: identification of 4-[4-[4-(aminoiminomethyl)phenyl]-1-piperazinyl]-1-piperidineacetic acid as a long-acting, broad-spectrum antithrombotic agent. J Med Chem 37: 3882-5 [PMID:7966149]
13. Fagerholm SC, Guenther C, Llort Asens M, Savinko T and Uotila LM. (2019) Beta2-Integrins and Interacting Proteins in Leukocyte Trafficking, Immune Suppression, and Immunodeficiency Disease. Front Immunol 10: 254 [PMID:30837997]
14. Fong S and Dennis MS.. (2009) Humanized anti-beta7 antagonists and uses therefor. Patent number: US7528236 B2. Assignee: Genentech, Inc.. Priority date: 03/09/2004. Publication date: 09/05/2009.
15. Fukase H, Kajioka T, Oikawa I, Ikeda N and Furuie H. (2020) AJM300, a novel oral antagonist of α4-integrin, sustains an increase in circulating lymphocytes: A randomised controlled trial in healthy male subjects. Br J Clin Pharmacol 86: 591-600 [PMID:31658381]
16. Goodman SL, Hölzemann G, Sulyok GA and Kessler H. (2002) Nanomolar small molecule inhibitors for alphav(beta)6, alphav(beta)5, and alphav(beta)3 integrins. J Med Chem 45: 1045-51 [PMID:11855984]
17. Grove RA, Shackelford S, Sopper S, Pirruccello S, Horrigan J, Havrdova E, Gold M and Graff O. (2013) Leukocyte counts in cerebrospinal fluid and blood following firategrast treatment in subjects with relapsing forms of multiple sclerosis. Eur J Neurol 20: 1032-42 [PMID:23419064]
18. Han J, Liu S, Rose DM, Schlaepfer DD, McDonald H and Ginsberg MH. (2001) Phosphorylation of the integrin alpha 4 cytoplasmic domain regulates paxillin binding. J Biol Chem 276: 40903-9 [PMID:11533025]
19. Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, Pellicoro A, Raschperger E, Betsholtz C and Ruminski PG et al.. (2013) Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 19: 1617-24 [PMID:24216753]
20. Hijazi Y, Welker H, Dorr AE, Tang JP, Blain R, Renzetti LM and Abbas R. (2004) Pharmacokinetics, safety, and tolerability of R411, a dual alpha4beta1-alpha4beta7 integrin antagonist after oral administration at single and multiple once-daily ascending doses in healthy volunteers. J Clin Pharmacol 44: 1368-78 [PMID:15545307]
21. Hutchinson JH, Halczenko W, Brashear KM, Breslin MJ, Coleman PJ, Duong LT, Fernandez-Metzler C, Gentile MA, Fisher JE and Hartman GD et al.. (2003) Nonpeptide alphavbeta3 antagonists. 8. In vitro and in vivo evaluation of a potent alphavbeta3 antagonist for the prevention and treatment of osteoporosis. J Med Chem 46: 4790-8 [PMID:14561098]
22. Jardieu PM and Presta LG. (2004) Method of treatment using humanized anti-CD11a antibodies. Patent number: US6703018. Assignee: Genentech, Inc.. Priority date: 27/11/1996. Publication date: 19/03/2004.
23. Kelly TA, Jeanfavre DD, McNeil DW, Woska Jr JR, Reilly PL, Mainolfi EA, Kishimoto KM, Nabozny GH, Zinter R and Bormann BJ et al.. (1999) Cutting edge: a small molecule antagonist of LFA-1-mediated cell adhesion. J Immunol 163: 5173-7 [PMID:10553036]
24. Kishimoto TK, Hollander N, Roberts TM, Anderson DC and Springer TA. (1987) Heterogeneous mutations in the beta subunit common to the LFA-1, Mac-1, and p150,95 glycoproteins cause leukocyte adhesion deficiency. Cell 50: 193-202 [PMID:3594570]
25. Lee Y, Kang DK, Chang SI, Han MH and Kang IC. (2004) High-throughput screening of novel peptide inhibitors of an integrin receptor from the hexapeptide library by using a protein microarray chip. J Biomol Screen 9: 687-94 [PMID:15634795]
26. Liles WC, Dale DC, Price TH, Gaviria JM, Turner T, Saoud J and Frumkin LR. (2000) Inhibition of in vivo neutrophil transmigration by a novel humanized anti-CD11/CD18 monoclonal antibody. Cytokines Cell Mol Ther 6: 121-6 [PMID:11140880]
27. Lin Kc, Ateeq HS, Hsiung SH, Chong LT, Zimmerman CN, Castro A, Lee WC, Hammond CE, Kalkunte S and Chen LL et al.. (1999) Selective, tight-binding inhibitors of integrin alpha4beta1 that inhibit allergic airway responses. J Med Chem 42: 920-34 [PMID:10072689]
28. Liu G, Link JT, Pei Z, Reilly EB, Leitza S, Nguyen B, Marsh KC, Okasinski GF, von Geldern TW and Ormes M et al.. (2000) Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intracellular adhesion molecule-1 interaction. 1. Identification of an additional binding pocket based on an anilino diaryl sulfide lead. J Med Chem 43: 4025-40 [PMID:11052808]
29. Makino S, Okuzumi T, Yoshimura T, Satake Y, Suzuki N, Izawa H, Sagi K, Chiba A, Nakanishi E and Murata M et al.. (2011) New phenylalanine derivatives Patent number: US20110065918A1. Assignee: EA Pharma Co Ltd. Priority date: 18/08/2000. Publication date: 17/03/2011.
30. Marcinkiewicz C, Weinreb PH, Calvete JJ, Kisiel DG, Mousa SA, Tuszynski GP and Lobb RR. (2003) Obtustatin: a potent selective inhibitor of alpha1beta1 integrin in vitro and angiogenesis in vivo. Cancer Res 63: 2020-3 [PMID:12727812]
31. Matsuno H, Stassen JM, Vermylen J and Deckmyn H. (1994) Inhibition of integrin function by a cyclic RGD-containing peptide prevents neointima formation. Circulation 90: 2203-6 [PMID:7955174]
32. Miller MW, Basra S, Kulp DW, Billings PC, Choi S, Beavers MP, McCarty OJ, Zou Z, Kahn ML and Bennett JS et al.. (2009) Small-molecule inhibitors of integrin alpha2beta1 that prevent pathological thrombus formation via an allosteric mechanism. Proc Natl Acad Sci USA 106: 719-24 [PMID:19141632]
33. Nissinen L, Koivunen J, Käpylä J, Salmela M, Nieminen J, Jokinen J, Sipilä K, Pihlavisto M, Pentikäinen OT and Marjamäki A et al.. (2012) Novel α2β1 integrin inhibitors reveal that integrin binding to collagen under shear stress conditions does not require receptor preactivation. J Biol Chem 287: 44694-702 [PMID:23132859]
34. No authors listed. (2004) Natalizumab: AN 100226, anti-4alpha integrin monoclonal antibody. Drugs R D 5: 102-7 [PMID:15293871]
35. Pan WJ, Hsu H, Rees WA, Lear SP, Lee F, Foltz IN, Rathanaswami P, Manchulenko K, Chan BM and Zhang M et al.. (2013) Pharmacology of AMG 181, a human anti-α4 β7 antibody that specifically alters trafficking of gut-homing T cells. Br J Pharmacol 169: 51-68 [PMID:23425116]
36. Pepinsky RB, Mumford RA, Chen LL, Leone D, Amo SE, Riper GV, Whitty A, Dolinski B, Lobb RR and Dean DC et al.. (2002) Comparative assessment of the ligand and metal ion binding properties of integrins alpha9beta1 and alpha4beta1. Biochemistry 41: 7125-41 [PMID:12033947]
37. Ponath PD, Ringler DJ, ST, Newman W, Saldanha J and Bendig MM. (2006) Humanized immunoglobulin reactive with α4β7 integrin. Patent number: US7147851 B1. Assignee: Millennium Pharmaceuticals, Inc.. Priority date: 15/08/1996. Publication date: 12/12/2006.
38. Sato-Nishiuchi R, Nakano I, Ozawa A, Sato Y, Takeichi M, Kiyozumi D, Yamazaki K, Yasunaga T, Futaki S and Sekiguchi K. (2012) Polydom/SVEP1 is a ligand for integrin α9β1. J Biol Chem 287: 25615-30 [PMID:22654117]
39. Scarborough RM and Gretler DD. (2000) Platelet glycoprotein IIb-IIIa antagonists as prototypical integrin blockers: novel parenteral and potential oral antithrombotic agents. J Med Chem 43: 3453-73 [PMID:10999999]
40. Soler D, Chapman T, Yang LL, Wyant T, Egan R and Fedyk ER. (2009) The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther 330: 864-75 [PMID:19509315]
41. Stefanich EG, Danilenko DM, Wang H, O'Byrne S, Erickson R, Gelzleichter T, Hiraragi H, Chiu H, Ivelja S and Jeet S et al.. (2011) A humanized monoclonal antibody targeting the β7 integrin selectively blocks intestinal homing of T lymphocytes. Br J Pharmacol 162: 1855-70 [PMID:21232034]
42. Sun B, Chen Q, Dong X, Liu D, Hou J, Wang W, Ying W, Hui X, Zhou Q and Yao H et al.. (2019) Report of a Chinese Cohort with Leukocyte Adhesion Deficiency-I and Four Novel Mutations. J Clin Immunol 39: 309-315 [PMID:30919141]
43. Trstenjak U, Ilaš J and Kikelj D. (2013) Low molecular weight dual inhibitors of factor Xa and fibrinogen binding to GPIIb/IIIa with highly overlapped pharmacophores. Eur J Med Chem 64: 302-13 [PMID:23644213]
44. Wolf C, Sidhu J, Otoul C, Morris DL, Cnops J, Taubel J and Bennett B. (2013) Pharmacodynamic consequences of administration of VLA-4 antagonist CDP323 to multiple sclerosis subjects: a randomized, double-blind phase 1/2 study. PLoS One 8: e58438 [PMID:23472197]
45. Wu H and Gao C. (2010) Eph receptor Fc variants with enhanced antibody dependent cell-mediated cytotoxicity activity. Patent number: US7659374. Assignee: Medimmune, Llc. Priority date: 16/08/2004. Publication date: 09/02/2010.
46. Yao N, Xiao W, Wang X, Marik J, Park SH, Takada Y and Lam KS. (2009) Discovery of targeting ligands for breast cancer cells using the one-bead one-compound combinatorial method. J Med Chem 52: 126-33 [PMID:19055415]
47. Yasuda T, Gold HK, Kohmura C, Guerrero L, Yaoita H, Fallon JT, Bunting S and Collen D. (1993) Intravenous and endobronchial administration of G4120, a cyclic Arg-Gly-Asp-containing platelet GPIIb/IIIa receptor-blocking pentapeptide, enhances and sustains coronary arterial thrombolysis with rt-PA in a canine preparation. Arterioscler Thromb 13: 738-47 [PMID:8485125]
48. Yenari MA, Kunis D, Sun GH, Onley D, Watson L, Turner S, Whitaker S and Steinberg GK. (1998) Hu23F2G, an antibody recognizing the leukocyte CD11/CD18 integrin, reduces injury in a rabbit model of transient focal cerebral ischemia. Exp Neurol 153: 223-33 [PMID:9784282]
49. Zhong M, Gadek TR, Bui M, Shen W, Burnier J, Barr KJ, Hanan EJ, Oslob JD, Yu CH and Zhu J et al.. (2012) Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye. ACS Med Chem Lett 3: 203-6 [PMID:24900456]