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Small-molecule inhibitors for autoimmune arthritis: Success, failure and the future Ling-Jun Ho a, Jenn-Haung Lai b,c,n a

Institute of Cellular and System Medicine, National Health Research Institute, Zhunan, Taiwan, ROC Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan, ROC c Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Tao-Yuan, Taiwan, ROC b

art ic l e i nf o

a b s t r a c t

Article history: Received 20 April 2014 Received in revised form 21 August 2014 Accepted 24 August 2014

Treatment of patients with aggressive autoimmune arthritis, such as rheumatoid arthritis (RA), is a considerable challenge for physicians, particularly rheumatologists. Because of the nature of autoimmune arthritis, effective and complete suppression of disease activity has been the primary therapeutic goal. Although currently available disease-modifying antirheumatic drugs (DMARDs) can successfully control the disease progression in a large proportion of patients, the benefit/risk ratio is not very much satisfied. The introduction of biologic agents such as anti-tumor necrosis factor-α, antiinterleukin-6, and anti-CD20 brings significant help to those patients with an inadequate response to treatment with DMARDs. In considering the limitation of currently available DMARDs and biologics, the development of new DMARDs, small-molecule inhibitors (SMIs), has recently emerged. In the past few years, a great volume of knowledge has been revealed from the experience of examining the usefulness of several SMIs for therapeutics of autoimmune arthritis. This paper addresses the up-to-date knowledge regarding autoimmune arthritis, therapeutics, findings from recently developed SMIs and the benefits and drawbacks of the development of SMIs. In addition, perspectives on the future development of SMIs for autoimmune arthritis will be described and discussed. & 2014 Elsevier B.V. All rights reserved.

Keywords: Small-molecule inhibitors Autoimmune arthritis Janus kinases P38 Spleen tyrosine kinase Phosphodiesterase 4

1. Introduction

2. Current therapeutic strategies for autoimmune arthritis

Autoimmune diseases are a group of illnesses characterized by self-destructive processes that lead to systemic organ damages. Joint involvement (arthritis) is a common presentation for nearly all autoimmune disorders (hereby autoimmune arthritis), particularly so in the case of rheumatoid arthritis (RA), ankylosing spondylitis and psoriatic arthritis with joints as the primary target. Activation of immune effector cells such as macrophages, and T and B lymphocytes in autoimmune arthritis increases production of pro-inflammatory cytokines, chemokines, matrix metalloproteinases and many other proteinases that circulate in the bloodstream and accumulate in inflamed joints and cause joint destruction (Cooles and Isaacs, 2011). All these factors must be considered as a whole in developing therapies for autoimmune arthritis; otherwise, the therapeutic effect may be limited.

2.1. Cyclooxygenase inhibitor

n Corresponding author at: Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Tao-Yuan, Taiwan, ROC. Tel.: þ886 2 8792 7135; fax: þ 886 2 8792 7136. E-mail address: [email protected] (J.-H. Lai).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a major group of fundamental drugs used to attenuate various inflammation-associated pain, like arthritis. NSAIDs inhibit prostaglandin synthesis through blocking cyclooxygenase (COX) activity (Vane, 1971). The bifunctional prostaglandin endoperoxide synthase isozyme (PGHS)-1 (COX-1) and PGHS-2 (COX-2) pathway is one of the major pathways of arachidonic acid metabolism leading to inflammatory reaction. COX-3 is a splice-variant of COX1 with unclear roles in inflammation due to lack of COX activity in rodents and humans (Kis et al., 2005). It is generally accepted that the major adverse effects of NSAIDs such as gastrointestinal injury and renal function impairment are due to inhibition of COX-1, whereas the anti-inflammatory properties of NSAIDs are mainly from inhibition of COX-2. The COX-2-selective NSAIDs such as celecoxib, meloxicam and etoricoxib that preserve inhibitory selectivity on COX-2 have similar potency in pain-relief but less gastrointestinal and renal adverse events compared to those of conventional non-selective NSAIDs (Lee et al., 2005). 0014-2999/& 2014 Elsevier B.V. All rights reserved.

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2.2. Disease-modifying antirheumatic drugs Current therapeutic strategies for autoimmune arthritis like RA utilize a combination of different immunomodulatory agents called disease-modifying antirheumatic drugs (DMARDs) (O'Dell, 2013). The most commonly prescribed DMARDs for autoimmune arthritis are methotrexate (MTX), hydrooxychloroquine, sulfasalazine, azathioprine, cyclosporin and leflunomide. Because these DMARDs preserve different immunomodulatory effects and mechanisms in immune effector cells like T lymphocytes (Ho and Lai, 2004), a combination of these agents can achieve synergistic effects in prevention of disease progression and joint deformity as well as in preservation of functional capacity of the joints (Fleischmann, 2013; O'Dell et al., 2013). 2.3. Biologic agents Biologic agents, including those that target tumor necrosis factor (TNF, such as infliximab, adalimumab, certolizumab and golimumab), interleukin (IL)-1 (anakinra) and IL-6 (tocilizumab), inhibit the CD28 co-stimulatory signal (abatacept) or delete B cells (rituximab) are very useful and effective therapeutic modalities for patients with inadequate response to DMARDs (Choy et al., 2013; Smolen et al., 2014). Although the advantages of biologic agents are numerous, many limitations remain for all these biologics, including inconvenient administration (intravenous or subcutaneous injection), high cost and increased rates of infection, especially of tuberculosis and hepatitis (Dixon et al., 2010; Modena et al., 2013). Scientists in Sweden evaluated the socioeconomic impact of RA and concluded that there is a 32% increase in the total fixed cost of RA between 1990 and 2010, a period covering 10 years before and 10 years after introduction of biologic agents (Kalkan et al., 2014). The increase of economic burden after introduction of the biologic agents has been reported worldwide and, in general, the combination of DMARDs remains to be the most cost-effective option for RA treatment (Eriksson et al., 2014; Wu et al., 2012). Another drawback for the biologic agents is the induction of immunogenicity leading to generation of a highaffinity B cell-mediated humoral response directed against biologic agents that greatly reduces their therapeutic effects (van Schouwenburg et al., 2013).

3. Recently developed small molecule inhibitors (SMIs) for autoimmune arthritis: failure and success SMIs are a new generation of DMARDs. Given that the molecular targets and immunomodulatory mechanisms of many DMARDs remain unclear, SMIs are designed to target molecules of specific signaling pathways and/or mechanisms in cell activation (O'Shea et al., 2013b). In addition to targeting extracellular molecules, SMIs can specifically target intracellular molecules such as kinases, phosphatases, adaptors, scaffold proteins, transcription factors, and nuclear proteins. By interfering with the function of these signaling molecules, SMIs can change cellular structure, suppress cell growth, cell–cell interactions, signal transduction, gene transcription and protein translation or induce cellular death (O'Shea et al., 2013a). Cross-species contamination is also greatly reduced in SMIs. 3.1. p38 inhibitor By observing that pyridinyl-imidazole compounds can inhibit production of IL-1 and TNF from stimulated human monocytes, using radiolabeled and radio-photoaffinity-labeled chemical probes, Lee et al. identified p38 as the target of these compounds

(Lee et al., 1994). A variety of inflammatory stimuli or conditions, including pro-inflammatory cytokines, physicochemical stress, shock and infection, can induce signals through p38 in immune effector cells and synovial fibroblasts (Hope et al., 2009; Lee and Young, 1996). In mammalian cells, there are four isoforms of p38, namely p38α, p38β, p38γ, and p38δ. Different from both γ and δ isoforms that are mainly localized in certain specific tissues, the α and β isoforms are ubiquitous (Ono and Han, 2000). The roles of p38 isoforms have been investigated by genetic approaches. Compared to the knockout of p38α that is embryonically lethal (Allen et al., 2000), animals with the deficiency of p38β, p38γ or p38δ are viable, fertile and healthy (Beardmore et al., 2005; Sabio et al., 2005). In addition, a knockout of the p38β gene does not affect lipopolysaccharide (LPS)-induced cytokine production and development of TNF-induced arthritis (Beardmore et al., 2005). The inducible deletion of p38α in adult human TNF-transgenic mice, which avoids the embryonic lethality, decreases severity of arthritis and protects against TNFα-induced bony destruction (Bohm et al., 2009). However, a specific deletion of p38α in macrophages inhibits LPS-induced TNFα but not IL-6 production and has no effect on LPS-induced NF-κB activation (Kang et al., 2008). Analysis on inflamed tissues from patients with RA showed that p38α and p38γ among p38 isoforms are the major p38 isoforms activated in joint inflammation (Korb et al., 2006). In addition, IL-1β can activate both p38α and p38γ isoforms in human OA chondrocytes (Rasheed et al., 2010). Interestingly, recent studies showed that compound deficiency of p38γ and p38δ significantly reduces collagen-induced arthritis and expression of pro-inflammatory cytokines such as IL-1, TNFα and IL-17; however, a deficiency of either p38γ or p38δ has only intermediate inhibitory effect (Criado et al., 2014). Evidently, the role of p38γ in joint inflammation needs to be further investigated. Because accumulated studies suggest that p38α appears to be the most important molecule among p38 isoforms in inflammatory response, many potent p38α inhibitors preserving antiinflammatory properties were developed and at least 22 of which were investigated in phase I/II clinical trials for many autoimmune diseases. However, none of them progressed to phase III trials because of limited clinical efficacy and potential adverse events such as liver toxicities, serious infections, gastrointestinal disorders, and central nervous system disorders (Damjanov et al., 2009; Goldstein et al., 2010; Hammaker and Firestein, 2010; Terajima et al., 2013). Although the use of p38 inhibitors proved disappointing in treatment of autoimmune arthritis, their applications in other diseases warrant evaluation (Buhler and Laufer, 2014). The failure of many p38α inhibitors in clinical trials due to lack of therapeutic efficacy and unacceptable drug toxicities in RA patients is somewhat un-expected. Several reasons such as inadequate dosing exposure, the potential anti-inflammatory property of p38α, the reduced lipophilicity and CNS penetration in drug designs, the redundant upstream signaling networks resulting in escape from p38 regulation have been proposed (Hammaker and Firestein, 2010). In addition, similar to the example of the protein kinase C isoforms (Fan et al., 2014), either pro- or antiinflammatory effects of p38 isoforms may be present depending on their expressions in certain specific tissues and the signals triggered to activate these kinases (Chakravarty et al., 2013). For example, myeloid p38α is required for inflammatory infiltration, epidermal hyperproliferation, and hyperkeratosis in mice with chronic sodium dodecyl sulfate-induced skin injury (Kim et al., 2008). In contrast, given that p38α signaling in keratinocytes drives UVB-induced epidermal injury, myeloid p38α reduces UVB-induced vascular hyperpermeability (Kim et al., 2008). Nevertheless, the experience from p38α inhibitors and JAK inhibitors (discussed below) suggests a possibility that higher level of inhibition may extend therapeutic efficacy and not necessary

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bring more adverse events as proposed earlier (Ghoreschi et al., 2009). In contrast to the knockout of p38α that is lethal, the animals with deficiency of MAP kinase kinase (MMK)3, a kinase upstream of p38, are viable and healthy (Inoue et al., 2006). And yet, the animals are protective from passively induced arthritis. Similar observations were also demonstrated in animals with deficiency of MMK6 (Yoshizawa et al., 2009).

3.2. Janus kinases inhibitor (tofacitinib) The Janus kinases (JAKs), JAK1, JAK2, JAK3 and Tyk2, play pivotal roles in many pro-inflammatory cytokines-stimulated signaling pathways leading to activation of MAPKs and NF-κB (Bezbradica and Medzhitov, 2009). Tofacitinib (CP 690550) inhibits JAKs and preserves the functional specificity for JAK1 and JAK3 over JAK2 (Changelian et al., 2008). Aiming at RA patients with an inadequate response to at least one biologic or non-biologic DMARDs, tofacitinib treatment significantly reduces symptoms and signs and improves physical function of RA patients (Fleischmann et al., 2012). In combination with MTX, tofacitinib was effective in patients with moderate-to-severe RA who has an inadequate response to anti-TNF treatments (Burmester et al., 2013). Unfortunately, compared to the placebo-treated group, the proportions of patients in the tofacitinib group who met the criterion for disease remission (a score of o2.6 on the disease activity score (DAS)28-4[ESR]) were not significantly increased (Fleischmann et al., 2012).

3.3. Phosphodiesterase 4 inhibitor The cyclic nucleotides cAMP and cGMP are important intracellular secondary messengers mediating signal transductions for a variety of stimuli, including those critical in inflammatory responses (Conti and Beavo, 2007). Increased intracellular cAMP activates protein kinase A and results in activation of transcription factors such as cAMP responsive element binding protein and activator protein-1, while inhibiting activity of NF-κB (Jimenez et al., 2001; Ollivier et al., 1996). Thus, through regulating cAMP levels, immune homeostasis is maintained: high intracellular cAMP reduces inflammation and depletion of cAMP levels exaggerates inflammation. The intracellular levels of cAMP are tightly controlled by two enzymes, namely adenylyl cyclase that promotes cAMP formation, and cyclic nucleotide phosphodiesterases (PDEs) that degrade cAMP. At least 11 distinct families of cAMP and/or cGMP-selective PDEs have been reported and among them, in most mammalian cells, PDE3 and PDE4 mainly target and hydrolyze cAMP (Francis et al., 2011). Inhibition of PDE4, which is more cAMP-specific than PDE3, activity increases intracellular cAMP levels and leads to down-regulation of the inflammatory responses by reducing pro-inflammatory cytokines, including TNFα, interferon-γ, IL-12 and IL-23 and increasing antiinflammatory cytokines, like IL-10 in different immune effector cells (Schafer, 2012). A phase 3 study examining the efficacy of apremilast, an oral PDE4 inhibitor, in patients with psoriatic arthritis demonstrated significant improvement in symptoms and signs with an acceptable safety profile and the drug was generally well-tolerated (Kavanaugh et al., 2014). Apremilast (Otezla((R))) has gained approval for treatment of active psoriatic arthritis in adults in the USA. Currently, additional targeted inflammatory diseases for PDE4 inhibitors such as ankylosing spondylitis, inflammatory bowel disease, sarcoidosis, atopic dermatitis, and RA are under phase 2 or phase 3 clinical investigation (Kumar et al., 2013; Poole and Ballantyne, 2014).


3.4. Bruton's tyrosine kinase (Btk) inhibitor Antibody production is regulated by distinct immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors such as B cell antigen receptor and Fc receptors on B cells. ITAM signaling causes integration of a common pathway regulated by several non-receptor tyrosine kinases, including Bruton's tyrosine kinase (Btk), thereby activating downstream molecules like phospholipase Cγ2 (Tan et al., 2013). Inhibition of Btk blocks B cell receptor-dependent B cell proliferation and reduces autoantibody levels in collagen-induced arthritis (Di Paolo et al., 2011). In rat models of adjuvant-induced arthritis, the Btk inhibitor RN486, alone or in combination with methotrexate, significantly reduced arthritis severity and systemic inflammation (Xu et al., 2012). Currently, several inhibitors of Btk are under investigation or under early phases of clinical trials for their effectiveness in RA patients (Whang and Chang, 2014).

3.5. Spleen tyrosine kinase (Syk) inhibitor Like Btk, Syk is a non-receptor protein tyrosine kinase expressed mainly in bone marrow-derived cells. Stimulated by pro-inflammatory cytokines like TNFα and IL-1, Syk activates JNK, induces expressions of MMPs and IL-6 and mediates joint destruction in animal models (Cha et al., 2006; Pine et al., 2007). Fostamatinib (R788) is a pro-drug of the active Syk inhibitor R406 and has been clinically evaluated for its potential in the treatment of RA patients with an inadequate response to MTX or biologic agents. Although significant improvement was observed at American College of Rheumatology (ACR)20 (20% improvement in disease symptoms/signs and disease activity), ACR50 and ACR70 in patients receiving fostamatinib compared to those receiving placebo in MTX-resistant group (Weinblatt et al., 2010), fostamatinib did not provide a significant therapeutic benefit, as compared with placebo, among biologic-resistant RA patients (Nijjar et al., 2013). Current evidence indicates that extensive studies of the benefit/risk effects of Syk inhibitor are warranted.

3.6. Other potential targets for SMIs While looking for more potent and safer SMIs is continuously undergoing, several potential molecular targets for SMIs are emerging. By using a computer-aided drug design, a lead compound (E)-4-(2-(4-chloro-3-nitrophenyl), which directly binds to TNFα and inhibits TNFα-triggered signaling activities, has been developed (Ma et al., 2014). Phosphoinositide 3-kinase (Tamura, 2012) is another potential anti-arthritis candidates shown in cellbased studies and in arthritis models in animals. High-mobility group box-1 (HMGB1) contributes to the pathogenesis of RA and systemic lupus erythematosus, through interaction with the cell surface receptor for advanced glycation end products (RAGE). By blocking RAGE–HMGB1 signaling, SMIs like glycyrrhizin and gabexate mesilate (which directly binds HMGB1) have potential in autoimmune arthritis therapeutics (Musumeci et al., 2014). Furthermore, Al-Riyami et al. synthesized a library of drug-like small molecules based on phosphorylcholine and found that a sulfone-containing phosphorylcholine analog downregulated the TLR/IL-1R transducer, myeloid differentiation primary response gene 88 (MyD88), and protected mice against development of collagen-induced arthritis (Al-Riyami et al., 2013). The targets of SMIs and the associated signaling pathways in B cell activation according to the publications (Jabara et al., 2012; Mocsai et al., 2010; Tan et al., 2013; Troutman et al., 2012) are briefly presented in Fig. 1.

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Fig. 1. Targets of SMIs and associated signaling pathways in B cell activation as an example. Treatment with anti-CD20 monoclonal antibody Rituximab to deplete B cells at certain-stages of development for patients with RA has been very successful. Thus, B cell is chosen as an example here. Many different signaling pathways are involved in the activation of B cells. Shown here includes only some common and important B cell activation pathways. Depending on different initiating signals, these pathways differentially or cooperatively regulate the activation of MAP kinases, including JNK, p38 and ERK as well as the downstream transcription factors such as NF-κB, AP-1, NFAT and STAT. Among the molecules shown here, some of them have been developed clinically for the treatment of autoimmune arthritis and some are undergoing early phases of clinical trials and they are shown in brown color. BCR, B cell receptor; BAFF, B cell activating factor (also known as BLYS, B lymphocyte stimulator); BCMA, B cell maturation antigen; TLR, toll-like receptor; FcR, Fc receptor; CR, cytokine receptor; TRAF, tumor necrosis factor receptor-associated factor; Syk, spleen tyrosine kinase; BTK, Bruton's tyrosine kinase; PI3K, phosphoinositide 3-kinase; MyD88, myeloid differentiation primary response gene 88; JAK, Janus kinase; MKK, mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; NF-κB, nuclear factor-κB; NFAT, nuclear factor of activated T cells; STAT, signal transducers and activators of transcription.

4. Future direction and conclusion Several newly established techniques and concepts can be applied along the way of development of SMIs. Through computational screening by combining docking and molecular dynamics simulations, researchers were capable of identifying specific and more effective lead compounds for specific purposes (Okimoto et al., 2009). In order to overcome the effects from non-specific bindings, new approaches measuring drug affinity responsive target stability and aiming to discover the direct binding targets (and off targets) of small molecules on a proteome scale in the absence of chemical modification of the compound have been developed (Lomenick et al., 2011). Under the aid of advanced material designs, it is possible to control the release kinetics of drugs to ensure that the therapeutic effect appears at the appropriate time (Laurencin and Khan, 2012). As the work continues, by building an efficient compound library and using an expanded kinase-profiling assay, researchers can identify more powerful and less toxic lead compounds for therapeutic purposes (Liou et al., 2014; Terajima et al., 2013). Developing a new drug is costly and very time-consuming. Current DMARDs are medications commonly prescribed for other well-known non-autoimmune disorders like cancer (MTX), infection (hydrooxychloroquine) and transplantation rejection (azathioprine and cyclosporin). By adjusting dosage and frequency of administration, DMARDs become the main therapeutic regimens for autoimmune arthritis patients. It is therefore highly anticipated to develop regimens specifically and uniquely for the treatment of autoimmune arthritis. SMIs are therefore very

attractive, especially for patients who do not respond adequately to traditional DMARDs or biologic agents.

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Please cite this article as: Ho, L.-J., Lai, J.-H., Small-molecule inhibitors for autoimmune arthritis: Success, failure and the future. Eur J Pharmacol (2014),

Small-molecule inhibitors for autoimmune arthritis: success, failure and the future.

Treatment of patients with aggressive autoimmune arthritis, such as rheumatoid arthritis (RA), is a considerable challenge for physicians, particularl...
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