Skip to main content
SpringerLink
Log in

Small-Molecule Inhibitors of Necroptosis

  • Chapter
  • First Online:
Necrotic Cell Death

Part of the book series: Cell Death in Biology and Diseases ((CELLDEATH))

  • 1609 Accesses

Abstract

Necroptosis is a novel form of programmed cell death that has been implicated in many disease states including ischemia–reperfusion injuries, brain trauma, pancreatitis, as well as inflammatory diseases such as systemic inflammatory response syndrome. Work done in recent years has shown that necroptosis is a highly regulated process with complex signaling pathways involved in both the initiation and execution of death. A number of signaling proteins, most importantly RIP1 and RIP3 kinases, have been discovered to be involved in signal transduction during necroptosis. Modulation of early steps of necroptosis could represent a critical method to develop new treatments for multiple diseases that have been associated with this process. In order to fully take advantage of the treatment opportunity associated with necroptosis, a thorough understanding of both the signaling pathways involved and ways to develop selective therapeutic modulators of necroptosis is critical. In this review we discuss inhibitors of necroptosis that are currently being developed and additional possible targets for manipulation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Andrabi S, Gjoerup OV, Kean JA, Roberts TM, Schaffhausen B (2007) Protein phosphatase 2A regulates life and death decisions via Akt in a context-dependent manner. Proc Natl Acad Sci U S A 104:19011–19016

    Article  PubMed Central  PubMed  Google Scholar 

  • Andrabi SA, Dawson TM, Dawson VL (2008) Mitochondrial and nuclear cross talk in cell death: parthanatos. Ann N Y Acad Sci 1147:233–241

    Article  PubMed  CAS  Google Scholar 

  • Benedetti A, Comporti M, Esterbauer H (1980) Identification of 4-hydroxynonenal as a cytotoxic product originating from the peroxidation of liver microsomal lipids. Biochim Biophys Acta 620:281–296

    Article  PubMed  CAS  Google Scholar 

  • Bogoyevitch MA, Ngoei KR, Zhao TT, Yeap YY, Ng DC (2010) c-Jun N-terminal kinase (JNK) signaling: recent advances and challenges. Biochim Biophys Acta 1804:463–475

    Article  PubMed  CAS  Google Scholar 

  • Bonnet MC, Preukschat D, Welz PS, van Loo G, Ermolaeva MA, Bloch W, Haase I, Pasparakis M (2011) The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation. Immunity 35:572–582

    Article  PubMed  CAS  Google Scholar 

  • Byun HS, Park KA, Won M, Yang KJ, Shin S, Piao L, Kwak JY, Lee ZW, Park J, Seok JH et al (2006) Phorbol 12-myristate 13-acetate protects against tumor necrosis factor (TNF)-induced necrotic cell death by modulating the recruitment of TNF receptor 1-associated death domain and receptor-interacting protein into the TNF receptor 1 signaling complex: Implication for the regulatory role of protein kinase C. Mol Pharmacol 70:1099–1108

    Article  PubMed  CAS  Google Scholar 

  • Cauwels A, Janssen B, Waeytens A, Cuvelier C, Brouckaert P (2003) Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2. Nat Immunol 4:387–393

    Article  PubMed  CAS  Google Scholar 

  • Chan TO, Rittenhouse SE, Tsichlis PN (1999) AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annu Rev Biochem 68:965–1014

    Article  PubMed  CAS  Google Scholar 

  • Chen TY, Chi KH, Wang JS, Chien CL, Lin WW (2009) Reactive oxygen species are involved in FasL-induced caspase-independent cell death and inflammatory responses. Free Radic Biol Med 46:643–655

    Article  PubMed  CAS  Google Scholar 

  • Chen SY, Chiu LY, Maa MC, Wang JS, Chien CL, Lin WW (2011) zVAD-induced autophagic cell death requires c-Src-dependent ERK and JNK activation and reactive oxygen species generation. Autophagy 7:217–228

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Chen W, Zhou Z, Li L, Zhong CQ, Zheng X, Wu X, Zhang Y, Ma H, Huang D, Li W et al (2013) Diverse sequence determinants control human and mouse receptor interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) interaction in necroptotic signaling. J Biol Chem 288:16247–16261

    Article  PubMed  CAS  Google Scholar 

  • Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, Chan FK (2009) Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137:1112–1123

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Christofferson DE, Yuan J (2010) Necroptosis as an alternative form of programmed cell death. Curr Opin Cell Biol 22:263–268

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Christofferson DE, Li Y, Hitomi J, Zhou W, Upperman C, Zhu H, Gerber SA, Gygi S, Yuan J (2012) A novel role for RIP1 kinase in mediating TNFalpha production. Cell Death Dis 3:e320

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Cifuentes-Pagano E, Csanyi G, Pagano PJ (2012) NADPH oxidase inhibitors: a decade of discovery from Nox2ds to HTS. Cell Mol Life Sci 69:2315–2325

    Article  PubMed  CAS  Google Scholar 

  • Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1:112–119

    Article  PubMed  CAS  Google Scholar 

  • Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G et al (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 4:313–321

    Article  PubMed  CAS  Google Scholar 

  • Degterev A, Maki JL, Yuan J (2013) Activity and specificity of necrostatin-1, small-molecule inhibitor of RIP1 kinase. Cell Death Differ 20:366

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Di Paolo NC, Doronin K, Baldwin LK, Papayannopoulou T, Shayakhmetov DM (2013) The transcription factor IRF3 triggers “Defensive Suicide” necrosis in response to viral and bacterial pathogens. Cell Rep 3(6):1840–1846

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Duprez L, Takahashi N, Van Hauwermeiren F, Vandendriessche B, Goossens V, Vanden Berghe T, Declercq W, Libert C, Cauwels A, Vandenabeele P (2011) RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity 35:908–918

    Article  PubMed  CAS  Google Scholar 

  • Fanjul A, Dawson MI, Hobbs PD, Jong L, Cameron JF, Harlev E, Graupner G, Lu XP, Pfahl M (1994) A new class of retinoids with selective inhibition of AP-1 inhibits proliferation. Nature 372:107–111

    Article  PubMed  CAS  Google Scholar 

  • Fiers W, Beyaert R, Boone E, Cornelis S, Declercq W, Decoster E, Denecker G, Depuydt B, De Valck D, De Wilde G et al (1995) TNF-induced intracellular signaling leading to gene induction or to cytotoxicity by necrosis or by apoptosis. J Inflamm 47:67–75

    PubMed  CAS  Google Scholar 

  • Galluzzi L, Vanden Berghe T, Vanlangenakker N, Buettner S, Eisenberg T, Vandenabeele P, Madeo F, Kroemer G (2011) Programmed necrosis from molecules to health and disease. Int Rev Cell Mol Biol 289:1–35

    Article  PubMed  CAS  Google Scholar 

  • Goossens V, Grooten J, De Vos K, Fiers W (1995) Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity. Proc Natl Acad Sci U S A 92:8115–8119

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Gunther C, Martini E, Wittkopf N, Amann K, Weigmann B, Neumann H, Waldner MJ, Hedrick SM, Tenzer S, Neurath MF et al (2011) Caspase-8 regulates TNF-alpha-induced epithelial necroptosis and terminal ileitis. Nature 477:335–339

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Hayakawa M, Ishida N, Takeuchi K, Shibamoto S, Hori T, Oku N, Ito F, Tsujimoto M (1993) Arachidonic acid-selective cytosolic phospholipase A2 is crucial in the cytotoxic action of tumor necrosis factor. J Biol Chem 268:11290–11295

    PubMed  CAS  Google Scholar 

  • He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X (2009) Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 137:1100–1111

    Article  PubMed  CAS  Google Scholar 

  • Heinrich M, Wickel M, Schneider-Brachert W, Sandberg C, Gahr J, Schwandner R, Weber T, Saftig P, Peters C, Brunner J et al (1999) Cathepsin D targeted by acid sphingomyelinase-derived ceramide. EMBO J 18:5252–5263

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Hernandes MS, Britto LR (2012) NADPH oxidase and neurodegeneration. Curr Neuropharmacol 10:321–327

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Hildebrand JM, Sun L, Silke J (2013) An appointment with death, 生死有旴: 2013 Cold Spring Harbor Asia meeting ‘Mechanisms and Functions of Non-Apoptotic Cell Death’. Cell Death Differ 20:1593–1594

    Google Scholar 

  • Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A, Xavier RJ, Yuan J (2008) Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135:1311–1323

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B, Tschopp J (2000) Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 1:489–495

    Article  PubMed  CAS  Google Scholar 

  • Jagtap PG, Degterev A, Choi S, Keys H, Yuan J, Cuny GD (2007) Structure-activity relationship study of tricyclic necroptosis inhibitors. J Med Chem 50:1886–1895

    Article  PubMed  CAS  Google Scholar 

  • Jin S, DiPaola RS, Mathew R, White E (2007) Metabolic catastrophe as a means to cancer cell death. J Cell Sci 120:379–383

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Jouan-Lanhouet S, Arshad MI, Piquet-Pellorce C, Martin-Chouly C, Le Moigne-Muller G, Van Herreweghe F, Takahashi N, Sergent O, Lagadic-Gossmann D, Vandenabeele P et al (2012) TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation. Cell Death Differ 19:2003–2014

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Kang TB, Yang SH, Toth B, Kovalenko A, Wallach D (2013) Caspase-8 blocks kinase RIPK3-mediated activation of the NLRP3 inflammasome. Immunity 38:27–40

    Article  PubMed  CAS  Google Scholar 

  • Kawahara A, Ohsawa Y, Matsumura H, Uchiyama Y, Nagata S (1998) Caspase-independent cell killing by Fas-associated protein with death domain. J Cell Biol 143:1353–1360

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Kim YS, Morgan MJ, Choksi S, Liu ZG (2007) TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Mol Cell 26:675–687

    Article  PubMed  CAS  Google Scholar 

  • Kim YJ, Kim EH, Hahm KB (2012) Oxidative stress in inflammation-based gastrointestinal tract diseases: challenges and opportunities. J Gastroenterol Hepatol 27:1004–1010

    Article  PubMed  CAS  Google Scholar 

  • Laster SM, Wood JG, Gooding LR (1988) Tumor necrosis factor can induce both apoptotic and necrotic forms of cell lysis. J Immunol 141:2629–2634

    PubMed  CAS  Google Scholar 

  • Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, Damko E, Moquin D, Walz T, McDermott A et al (2012) The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150:339–350

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Lin J, Li H, Yang M, Ren J, Huang Z, Han F, Huang J, Ma J, Zhang D, Zhang Z et al (2013) A role of RIP3-mediated macrophage necrosis in atherosclerosis development. Cell Rep 3:200–210

    Article  PubMed  CAS  Google Scholar 

  • Linkermann A, Brasen JH, Himmerkus N, Liu S, Huber TB, Kunzendorf U, Krautwald S (2012) Rip1 (receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury. Kidney Int 81:751–761

    Article  PubMed  CAS  Google Scholar 

  • Lukens JR, Vogel P, Johnson GR, Kelliher MA, Iwakura Y, Lamkanfi M, Kanneganti TD (2013) RIP1-driven autoinflammation targets IL-1alpha independently of inflammasomes and RIP3. Nature 498:224–227

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Luschen S, Ussat S, Scherer G, Kabelitz D, Adam-Klages S (2000) Sensitization to death receptor cytotoxicity by inhibition of fas-associated death domain protein (FADD)/caspase signaling. Requirement of cell cycle progression. J Biol Chem 275:24670–24678

    Article  PubMed  CAS  Google Scholar 

  • Madamanchi NR, Runge MS (2013) Redox signaling in cardiovascular health and disease. Free Radic Biol Med 61C:473–501

    Article  PubMed  CAS  Google Scholar 

  • Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129:1261–1274

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • McNamara CR, Degterev A (2011) Small-molecule inhibitors of the PI3K signaling network. Future Med Chem 3:549–565

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • McNamara CR, Ahuja R, Osafo-Addo AD, Barrows D, Kettenbach A, Skidan I, Teng X, Cuny GD, Gerber S, Degterev A (2013) Akt regulates TNFalpha synthesis downstream of RIP1 kinase activation during necroptosis. PLoS One 8:e56576

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Micheau O, Tschopp J (2003) Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114:181–190

    Article  PubMed  CAS  Google Scholar 

  • Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC (2005) Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med 11:312–319

    Article  PubMed  CAS  Google Scholar 

  • Narayan N, Lee IH, Borenstein R, Sun J, Wong R, Tong G, Fergusson MM, Liu J, Rovira II, Cheng HL et al (2012) The NAD-dependent deacetylase SIRT2 is required for programmed necrosis. Nature 492:199–204

    Article  PubMed  CAS  Google Scholar 

  • O’Donnell MA, Perez-Jimenez E, Oberst A, Ng A, Massoumi R, Xavier R, Green DR, Ting AT (2011) Caspase 8 inhibits programmed necrosis by processing CYLD. Nat Cell Biol 13:1437–1442

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Oerlemans MI, Liu J, Arslan F, den Ouden K, van Middelaar BJ, Doevendans PA, Sluijter JP (2012) Inhibition of RIP1-dependent necrosis prevents adverse cardiac remodeling after myocardial ischemia-reperfusion in vivo. Basic Res Cardiol 107:270

    Article  PubMed  CAS  Google Scholar 

  • Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet JC, McLean PJ et al (2007) Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson’s disease. Science 317:516–519

    Article  PubMed  CAS  Google Scholar 

  • Pyne S, Pyne NJ (2000) Sphingosine 1-phosphate signalling in mammalian cells. Biochem J 349:385–402

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Roca FJ, Ramakrishnan L (2013) TNF dually mediates resistance and susceptibility to mycobacteria via mitochondrial reactive oxygen species. Cell 153:521–534

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Rosenbaum DM, Degterev A, David J, Rosenbaum PS, Roth S, Grotta JC, Cuny GD, Yuan J, Savitz SI (2010) Necroptosis, a novel form of caspase-independent cell death, contributes to neuronal damage in a retinal ischemia-reperfusion injury model. J Neurosci Res 88:1569–1576

    PubMed  CAS  Google Scholar 

  • Saelens X, Festjens N, Parthoens E, Vanoverberghe I, Kalai M, van Kuppeveld F, Vandenabeele P (2005) Protein synthesis persists during necrotic cell death. J Cell Biol 168:545–551

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Schulze-Osthoff K, Bakker AC, Vanhaesebroeck B, Beyaert R, Jacob WA, Fiers W (1992) Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation. J Biol Chem 267:5317–5323

    PubMed  CAS  Google Scholar 

  • Shindo R, Kakehashi H, Okumura K, Kumagai Y, Nakano H (2013) Critical contribution of oxidative stress to TNFalpha-induced necroptosis downstream of RIPK1 activation. Biochem Biophys Res Commun 436(2):212–216

    Article  PubMed  CAS  Google Scholar 

  • Shulga N, Pastorino JG (2012) GRIM-19-mediated translocation of STAT3 to mitochondria is necessary for TNF-induced necroptosis. J Cell Sci 125:2995–3003

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Smith EL, Schuchman EH (2008) The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of common diseases. FASEB J 22:3419–3431

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Soldani C, Scovassi AI (2002) Poly(ADP-ribose) polymerase-1 cleavage during apoptosis: an update. Apoptosis 7:321–328

    Article  PubMed  CAS  Google Scholar 

  • Sosna J, Voigt S, Mathieu S, Lange A, Thon L, Davarnia P, Herdegen T, Linkermann A, Rittger A, Chan FK et al (2013) TNF-induced necroptosis and PARP-1-mediated necrosis represent distinct routes to programmed necrotic cell death. Cell Mol Life Sci 71:331–348

    Google Scholar 

  • Stephens LR, Jackson TR, Hawkins PT (1993) Agonist-stimulated synthesis of phosphatidylinositol(3,4,5)-trisphosphate: a new intracellular signalling system? Biochim Biophys Acta 1179:27–75

    Article  PubMed  CAS  Google Scholar 

  • Sun XM, Butterworth M, MacFarlane M, Dubiel W, Ciechanover A, Cohen GM (2004) Caspase activation inhibits proteasome function during apoptosis. Mol Cell 14:81–93

    Article  PubMed  CAS  Google Scholar 

  • Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X et al (2012) Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148:213–227

    Article  PubMed  CAS  Google Scholar 

  • Takahashi N, Duprez L, Grootjans S, Cauwels A, Nerinckx W, DuHadaway JB, Goossens V, Roelandt R, Van Hauwermeiren F, Libert C et al (2012) Necrostatin-1 analogues: critical issues on the specificity, activity and in vivo use in experimental disease models. Cell Death Dis 3:e437

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Teng X, Degterev A, Jagtap P, Xing X, Choi S, Denu R, Yuan J, Cuny GD (2005) Structure-activity relationship study of novel necroptosis inhibitors. Bioorg Med Chem Lett 15:5039–5044

    Article  PubMed  CAS  Google Scholar 

  • Teng X, Keys H, Jeevanandam A, Porco JA Jr, Degterev A, Yuan J, Cuny GD (2007) Structure-activity relationship study of [1,2,3]thiadiazole necroptosis inhibitors. Bioorg Med Chem Lett 17:6836–6840

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Thon L, Mohlig H, Mathieu S, Lange A, Bulanova E, Winoto-Morbach S, Schutze S, Bulfone-Paus S, Adam D (2005) Ceramide mediates caspase-independent programmed cell death. FASEB J 19:1945–1956

    Article  PubMed  CAS  Google Scholar 

  • Trichonas G, Murakami Y, Thanos A, Morizane Y, Kayama M, Debouck CM, Hisatomi T, Miller JW, Vavvas DG (2010) Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis. Proc Natl Acad Sci U S A 107:21695–21700

    Article  PubMed Central  PubMed  Google Scholar 

  • Upton JW, Kaiser WJ, Mocarski ES (2012) DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA. Cell Host Microbe 11:290–297

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Vanden Berghe T, Vanlangenakker N, Parthoens E, Deckers W, Devos M, Festjens N, Guerin CJ, Brunk UT, Declercq W, Vandenabeele P (2010) Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration features. Cell Death Differ 17:922–930

    Article  PubMed  CAS  Google Scholar 

  • Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11:700–714

    Article  PubMed  CAS  Google Scholar 

  • Vercammen D, Beyaert R, Denecker G, Goossens V, Van Loo G, Declercq W, Grooten J, Fiers W, Vandenabeele P (1998) Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J Exp Med 187:1477–1485

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Vince JE, Wong WW, Gentle I, Lawlor KE, Allam R, O’Reilly L, Mason K, Gross O, Ma S, Guarda G et al (2012) Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity 36:215–227

    Article  PubMed  CAS  Google Scholar 

  • Wallach D, Kovalenko A, Kang TB (2011) ‘Necrosome’-induced inflammation: must cells die for it? Trends Immunol 32:505–509

    Article  PubMed  CAS  Google Scholar 

  • Wang K, Li J, Degterev A, Hsu E, Yuan J, Yuan C (2007) Structure–activity relationship analysis of a novel necroptosis inhibitor, Necrostatin-5. Bioorg Med Chem Lett 17:1455–1465

    Article  PubMed  CAS  Google Scholar 

  • Wang Z, Jiang H, Chen S, Du F, Wang X (2012) The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell 148:228–243

    Article  PubMed  CAS  Google Scholar 

  • Welker ME, Kulik G (2013) Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors. Bioorg Med Chem 21:4063–4091

    Article  PubMed  CAS  Google Scholar 

  • Welz PS, Wullaert A, Vlantis K, Kondylis V, Fernandez-Majada V, Ermolaeva M, Kirsch P, Sterner-Kock A, van Loo G, Pasparakis M (2011) FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477:330–334

    Article  PubMed  CAS  Google Scholar 

  • Wu YT, Tan HL, Huang Q, Ong CN, Shen HM (2009) Activation of the PI3K-Akt-mTOR signaling pathway promotes necrotic cell death via suppression of autophagy. Autophagy 5:824–834

    PubMed  CAS  Google Scholar 

  • Wu YT, Tan HL, Huang Q, Sun XJ, Zhu X, Shen HM (2011) zVAD-induced necroptosis in L929 cells depends on autocrine production of TNFalpha mediated by the PKC-MAPKs-AP-1 pathway. Cell Death Differ 18:26–37

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Xie T, Peng W, Liu Y, Yan C, Maki J, Degterev A, Yuan J, Shi Y (2013) Structural basis of RIP1 inhibition by necrostatins. Structure 21:493–499

    Article  PubMed  CAS  Google Scholar 

  • Xu X, Chua CC, Zhang M, Geng D, Liu CF, Hamdy RC, Chua BH (2010) The role of PARP activation in glutamate-induced necroptosis in HT-22 cells. Brain Res 1343:206–212

    Article  PubMed  CAS  Google Scholar 

  • You Z, Savitz SI, Yang J, Degterev A, Yuan J, Cuny GD, Moskowitz MA, Whalen MJ (2008) Necrostatin-1 reduces histopathology and improves functional outcome after controlled cortical impact in mice. J Cereb Blood Flow Metab 28:1564–1573

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, Baehrecke EH, Lenardo MJ (2004) Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304:1500–1502

    Article  PubMed  CAS  Google Scholar 

  • Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, Dong MQ, Han J (2009) RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325:332–336

    Article  PubMed  CAS  Google Scholar 

  • Zhao J, Jitkaew S, Cai Z, Choksi S, Li Q, Luo J, Liu ZG (2012) Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc Natl Acad Sci U S A 109:5322–5327

    Article  PubMed Central  PubMed  Google Scholar 

  • Zhu S, Zhang Y, Bai G, Li H (2011) Necrostatin-1 ameliorates symptoms in R6/2 transgenic mouse model of Huntington’s disease. Cell Death Dis 2:e115

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Zou J, Kawai T, Tsuchida T, Kozaki T, Tanaka H, Shin KS, Kumar H, Akira S (2013) Poly IC triggers a cathepsin D- and IPS-1-dependent pathway to enhance cytokine production and mediate dendritic cell necroptosis. Immunity 38:717–728

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Graduate Program in Biochemistry, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, 02111, USA

    Colleen R. McNamara

  2. Department of Biochemistry, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, 02111, USA

    Alexei Degterev

Authors
  1. Colleen R. McNamara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexei Degterev
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexei Degterev .

Editor information

Editors and Affiliations

  1. Department of Physiology, National University of Singapore Yong Loo Lin School of Medicine, Singapore, Singapore

    Han-Ming Shen

  2. Department of Biomedical Molecular Biology (UGent), VIB/University of Ghent Inflammation Research Center (VIB), Zwijnaarde, Belgium

    Peter Vandenabeele

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

McNamara, C.R., Degterev, A. (2014). Small-Molecule Inhibitors of Necroptosis. In: Shen, HM., Vandenabeele, P. (eds) Necrotic Cell Death. Cell Death in Biology and Diseases. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-8220-8_17

Download citation

Publish with us

Policies and ethics

Search

Navigation