ReviewInflammation

SMAC mimetics and RIPK inhibitors as therapeutics for chronic inflammatory diseases

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Science Signaling  18 Feb 2020:
Vol. 13, Issue 619, eaax8295
DOI: 10.1126/scisignal.aax8295

Figures

  • Fig. 1 TLR4-dependent inflammatory signaling.

    Activation of the PRR TLR4 by LPS initiates downstream signaling through both TRIF- and MYD88-dependent pathways. The adaptor TRIF engages the kinase RIPK1 and the ubiquitin (Ub) ligase Pellino1, and ubiquitylation of RIPK1 by Pellino1 then enables recruitment of the kinase TAK1 and the TAK1-binding proteins TAB2/3 and the IκB kinase (IKK) complex. Consequently, TAK1 phosphorylates IKKβ of the IKK complex, leading to degradation of IκBα and allowing translocation of NF-κB into the nucleus. TRIF may also recruit the necrosome components RIPK1, RIPK3, and MLKL, leading to necroptosis. In MYD88-dependent TLR4 signaling, IRAKs, TRAF3, TRAF6, and cIAPs are recruited to the membrane. Autoubiquitylation of TRAF6 causes it to engage the TAB2/3-TAK1 and IKK complexes, leading to NF-κB activation. Activation of MAPKs and the downstream transcription factor AP1 requires translocation of the membrane complex into the cytosol, an event facilitated by cIAPs through K48-linked ubiquitylation of TRAF3. Administration of SMAC mimetics (SMs) induces the loss of cIAPs, thus disabling the cytosolic translocation of the signalosome and thereby interrupting MAPK activation.

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING
  • Fig. 2 NOD-dependent inflammatory signaling.

    After peptidoglycan (PGN) stimulation of NOD, RIPK2 is recruited to the receptor. Subsequently, XIAP is initially engaged and mediates K63-linked ubiquitylation (Ub) of RIPK2. This allows binding of linear ubiquitin chain assembly complex (LUBAC), which further ubiquitylates RIPK2 and other associated proteins, to recruit and activate the kinases IKK and TAK1 (41). These events culminate in both degradation of IκBα and hereby nuclear translocation of NF-κB and activation of MAPKs, leading to expression of AP1-responsive genes. Administration of XIAP-selective inhibitors [indicated by protein-protein interaction (PPI)] blocks binding of XIAP to RIPK2 disrupting downstream signaling. In addition, administration of RIPK2 inhibitors [indicated by kinase inhibitor (KI)] blocks the ability of RIPK2 to autophosphorylate and stabilize itself as well as blocking the binding of XIAP and hereby disabling important downstream ubiquitylations.

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING
  • Fig. 3 Canonical and noncanonical NF-κB signaling downstream of TNF superfamily receptors.

    Activation of TNFR1 by TNF-α induces the assembly of complex I, which includes TRADD, TRAF2 or TRAF5, RIPK1, and cIAPs. K63-linked autoubiquitylation (Ub) of cIAP facilitates the recruitment of LUBAC. cIAP-mediated K63-linked ubiquitylation of RIPK1 recruits the TAB2/3-TAK1 complex and the IKK complex. IKK complex recruitment is further facilitated through LUBAC-mediated, M1-linked ubiquitylation of RIPK1. Subsequently, TAK1 activates both canonical NF-κB and MAPK signaling pathways by phosphorylating IKKβ of the IKK complex and MAPKs, respectively. Other receptors for TNF superfamily ligands, such as the death receptor CD40, induce noncanonical NF-κB signaling. In the resting state, the noncanonical pathway is suppressed by the cytosolic cIAP-TRAF2-TRAF3 complex through cIAP-mediated ubiquitylation and subsequent degradation of NIK. Upon activation of CD40 by CD40L (also called CD154), the cIAP-TRAF2-TRAF3 complex is recruited to the membrane, where cIAP ubiquitylates TRAF3, leading to its degradation, as well as degradation of TRAF2 and cIAPs. Consequently, NIK accumulates and activates NF-κB. Administration of SMs inhibits canonical signaling, because recruitment of essential kinases is disabled. For the noncanonical pathway, administration of SM is predicted to inhibit NF-κB activation in the presence of ligand, because the cIAP-TRAF2-TRAF3 complex cannot be marked for degradation by Ub chains. Oppositely, SM administration is predicted to promote NF-κB activation in the absence of ligand because cIAPs can no longer ubiquitylate NIK for degradation.

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING
  • Fig. 4 Cell death pathways.

    Activation of TNFR1 by TNF-α stimulates canonical NF-κB signaling in a manner that depends on the assembly of complex I (TRADD, TRAF2 or TRAF5, RIPK1, and cIAPs) and on cIAP-mediated ubiquitylation (Ub) of RIPK1 (Fig. 3). If cIAPs are absent or inhibited by an SM or if RIPK1 is deubiquitylated, then stimulation of TNFR1 leads to the formation of complex II (also called the ripoptosome or death complex), resulting in cell death. This complex, comprising FADD, RIPK1, and caspase-8, can stimulate necroptosis or apoptosis. It promotes necroptosis by stimulating the formation of the necrosome (RIPK1, RIPK3, and MLKL), leading to phosphorylation and oligomerization of MLKL and disruption of the plasma membrane. Complex II promotes apoptosis by promoting the activation of caspases. Activation of death receptors, such as Fas, stimulates the recruitment of FADD and pro–caspase-8, which leads to cleavage and activation of caspase-8, thus enabling activation of the effector caspases (caspase-3 and caspase-7) that execute apoptosis. Cytokine death ligand pathways, like those induced by TNF-α or FasL, are known as extrinsic apoptosis. Intrinsic apoptosis, which is triggered by nonreceptor-mediated stimuli, such as DNA damage, involves mitochondrial release of cytochrome C (CytC) and SMAC. CytC is crucial for the formation of the apoptosome, which activates caspase-9, culminating in mitochondrial-mediated apoptosis by caspase-3 and caspase-7. XIAP inhibits caspase-3, caspase-7, and caspase-9 to prevent intrinsic apoptosis; inhibition of XIAP by endogenous SMAC or exogenous SM promotes apoptosis.

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING
  • Fig. 5 Mechanism of action of SMAC mimetics.

    (A) Monomeric cIAP is a catalytically inactive E3 ubiquitin ligase due to BIR3-mediated inhibition of the RING domain, which is necessary for dimerization and the recruitment of the E2 ubiquitin–conjugating enzyme. SMs disrupt this autoinhibition by binding to the BIR3 domain, resulting in RING domain dimerization, E2 binding, and catalytic activity. In the absence of a bona fide substrate to accept the ubiquitin (Ub), cIAP itself receives the proteasomal degradation tag. The stability of the active cIAP dimer is higher with dimeric SMs compared to monomeric SMs because intermolecular bridging strengthens the interaction and brings the two IAP molecules into closer proximity. (B) Dimeric SMs also mediate intramolecular bridging in XIAP by simultaneously binding to the BIR2 and BIR3 binding grooves, thereby preventing XIAP from binding to caspase-3/7 and caspase-9, respectively. RING, really interesting new gene; CARD, caspase-recruitment domain; UBA, ubiquitin-associated domain; BIR, baculoviral IAP repeat domain.

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING

Tables

  • Table 1 Ongoing and completed clinical trials with SMs.

    A list of all identifiable completed or ongoing clinical trials from searching the ClinicalTrials.gov and ClinicalTrialsRegister.eu databases and studies published as research papers (PubMed) or abstracts (Web of Science) by January 2020. Indications and reported side effects are listed. If a compound has been evaluated for the same indication in different trials, then only the trial representing the highest phase is listed. Studies terminated early are excluded. AML, acute myelogenous leukemia; CRC, colorectal cancer; CRS, cytokine release syndrome; DLT, dose-limiting toxicity; HNSCC, head and neck squamous cell carcinoma; MDS, myelodysplastic syndrome; NSCLC, non–small cell lung cancer; RCC, renal cell carcinoma; SCLC, small-cell lung cancer; TNBC, triple-negative breast cancer; N/A, not available; pts., patients.

    CompoundPhaseType of malignancyResultsClinical trial identifier
    (trial status)
    (publication)
    ASTX660*1AMLN/ANCT04155580
    (ongoing)
    1/2Solid tumors, lymphomaN/ANCT02503423
    (ongoing)
    BI 891065*1Solid tumors, NSCLCN/ANCT03166631
    (ongoing)
    CUDC-427*
    (formerly GDC-0917)
    1Solid tumors42 pts. Well-tolerated at
    5–600 mg/day
    Decreased cIAP1 abundance in
    PBMCs
    NCT01226277
    (completed)
    (109)
    DEBIO 1143*1Solid tumors, lymphoma51 pts. Well-tolerated <180
    mg/day. At higher dosage
    alanine aminotransferase
    was increased in 5% of pts.
    Decreased cIAP1 abundance
    in PBMCs
    NCT01078649
    (completed)
    (112)
    1Pancreatic cancer, CRCN/ANCT03871959
    (ongoing)
    1bSolid tumors, NSCLCN/ANCT03270176
    (ongoing)
    1/2HNSCCN/ANCT02022098
    (ongoing)
    1/2SCLC, HNSCC,
    gastrointestinal ovarian,
    endometrial, peritoneal, and
    cervical cancer
    N/ANCT04122625
    (ongoing)
    LCL-161*1Solid tumors71 pts. Well-tolerated up to
    1800 mg once/week with 9%
    experiencing CRS at higher
    concentrations, and in 6% of
    pts. as a DLT.
    cIAP1 degradation in
    peripheral tissue
    NCT01098838
    (completed)
    (111)
    2TNBC209 pts. Well-tolerated in
    combination with paclitaxel,
    although notable toxicity at
    1800 mg/week
    NCT01617668
    (completed)
    (113)
    2Multiple myeloma25 pts. Well-tolerated, but
    CRS observed in 4 of 11 pts.
    at 1800 mg/week. After dose
    reduction to 1200 mg/week,
    no further CRS was observed
    NCT01955434
    (completed)
    (117)
    1bCRC, NSCLC, TNBC, RCCN/ANCT02890069
    (ongoing)
    1/2SCLC, ovarian cancerN/ANCT02649673
    (ongoing)
    2LeukemiaN/ANCT02098161
    (ongoing)
    APG-13871/2Solid tumors, hematologic
    malignancies
    N/ANCT03386526
    (ongoing)
    Birinapant†1Solid tumors, lymphoma50 pts. Well-tolerated in
    dosages <35 mg/m2. At
    higher doses, CRS was
    observed in 5 of 12 pts. and
    Bell’s palsy in 2 of 3 pts.
    receiving 63 mg/m2.
    cIAP1 suppressed in PBMCs
    NCT00993239
    (completed)
    (114)
    1Ovarian cancer27 pts. Well-tolerated among
    89% of pts. 1 pt. got
    pancreatitis at an
    accumulated dose of
    78 mg/m2, and 1 pt. got
    Bell’s palsy at 104 mg/m2
    NCT01940172
    (completed)
    (115)
    1/2Solid tumors176 pts. Well-tolerated with
    ascending dose strategy
    <35 mg/m2. Bell’s palsy was
    observed in 8% of pts., yet
    lower risk than in the
    single-dosing group with no
    ascending strategy
    NCT01188499
    (completed)
    (110)
    1/2MDS21 pts. Well-tolerated at
    13 mg/m2 when combined
    with 5-azacitidine with side
    effects consistent with the
    disease under investigation.
    17% of evaluable pts.
    developed Bell’s palsy
    NCT01828346
    (completed)
    (116)
    1HNSCCN/ANCT03803774
    (ongoing)
    1/2AMLN/ANCT01486784
    (ongoing)
    HGS1029/ AEG408261Solid tumors66 pts. Well-tolerated at
    dosages up to 2.1 mg/m2
    Dose-related decrease of
    cIAP1 abundance in PBMCs
    NCT00708006
    (completed)
    (108)

    *Monovalent

    †Bivalent

    • Table 2 Ongoing and completed clinical trials with RIPK inhibitors.

      A list of all identifiable completed or ongoing clinical trials from searching the ClinicalTrials.gov and ClinicalTrialsRegister.eu databases and studies published as research papers (PubMed) or abstracts (Web of Science) by January 2020. Indications and reported side effects are listed. If a compound has been evaluated for the same indication in different trials, then only the trial representing the highest phase is listed. Early terminated studies have been excluded. ALS, amyotrophic lateral sclerosis; IBD, inflammatory bowel disease; RA, rheumatoid arthritis; UC, ulcerative colitis.

      CompoundTargetPhaseIndicationsResultsClinical trial identifier
      (trial status)
      (publication)
      GSK2982772 (GSK’772)RIPK11Intended for IBD79 healthy participants.
      Well-tolerated up to
      240 mg/day. Adverse
      events of mild intensity
      (most commonly
      contact dermatitis and
      headache).
      NCT02302404
      (completed)
      (158)
      RIPK11Intended for
      autoimmune diseases
      *NCT03266172
      (completed)
      RIPK11/2RA*NCT02858492
      (completed)
      RIPK12Psoriasis*NCT02776033
      (completed)
      RIPK12UCNot yet disclosedNCT02903966
      (completed)
      DNL747RIPK11Alzheimer’sNot yet disclosedNCT03757325
      (completed)
      RIPK11ALSN/ANCT03757351
      (ongoing)

      *Observations for pharmacokinetic studies available at ClinicalTrials.gov.

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