Advances in Targeting IKK and IKK-Related Kinases for Cancer Therapy Dung-Fang Lee1, 2 and Mien-Chie Hung1, 2

Molecular Pathways

Abstract InB kinases (IKK) and IKK-related kinases play critical roles in regulating the immune response through nuclear factor-nB and IFN regulatory factor ^ dependent signaling transduction cascades. Recently, these kinases have been implicated in the pathogenesis of many human diseases, including cancer. In fact, dysregulation of IKK activities promotes tumor survival, proliferation, migration, metastasis, and angiogenesisöcommon characteristics of many types of human cancers. Because of their oncogenic effects in human cancer development, targeting IKK and IKK-related kinases is becoming an increasingly popular avenue for the development of novel therapeutic interventions for cancer. This review will briefly cover the recent discovery of the downstream substrates of IKK and IKK-related kinases, and outline the strategies used for targeting IKK as a therapeutic intervention for cancer.

Nuclear factor-nB (NF-nB) transcriptional factors are initially tion through the E3 ligase h-transducing repeat-containing characterized central regulators and transcriptional factors in protein (h-TrCP)–mediated ubiquitin proteasome proteolysis. response to pathogens and viruses. Subsequently, NF-nB have The consequence of activation of the canonical pathway is been found to regulate a variety of genes involved in cell p50/RELA activation, which regulates cell proliferation, survival proliferation, migration, and survival, many of them have a migration, angiogenesis, and innate immune response. In role in tumor development and progression. In mammals, contrast, the noncanonical pathway is activated by other types there are five members of the NF-nB family, including RELA of inflammatory stimuli, including B cell–activating factor of (p65), RELB, c-REL, NF-nB1 (p105/p50), and NF-nB2 (p100/ the TNF family, lipopolysaccharide, and latent membrane p52), which associate with each other to form different protein 1, through IKKa homodimers which function inde- homodimers and heterodimers to regulate the expressions of pendently of the IKKa/IKKh/IKKg complex. This pathway is their downstream targets (1, 2). typified by phosphorylation of p100 and subsequent processes Several distinct NF-nB activation pathways have been to p52 through ubiquitin-dependent processing. The conse- identified. The two most frequently studied are the canonical quence of activation of the noncanonical pathway is p52/RELB (classic) and noncanonical (alternative) InB kinase (IKK)/NF- activation, which modulates B-cell development and adaptive nB pathways (Fig. 1). The canonical pathway is induced by immune response (1, 2). various inflammatory stimuli, such as tumor necrosis factor-a (TNFa), interleukin-1 (IL-1), and bacterial products (e.g., lipopolysaccharide) through the IKKa/IKKh/IKKg complex. Activation of the IKK Complex This pathway is classified by rapid phosphorylation of InBa, h an inhibitory protein retaining the NF-nB complex in the cyto- The IKK family contains five members, including IKKa,IKK, q plasm, at Ser32 and Ser36 by IKKh, and subsequent degrada- IKKg,IKK, and TANK-binding kinase 1 (TBK1). In contrast with IKKa,IKKh,IKKq, and TBK1, which function as kinases, IKKg lacks any kinase activities and functions as the regulatory subunit in the classic IKK complex, which contains IKKa and Authors’ Affiliations: 1Department of Molecular and Cellular Oncology, The IKKh (3). In response to proinflammatory stimuli, such as University of Texas M. D. Anderson Cancer Center and 2The University of Texas TNFa, IL-1, and toll-like receptor agonists (such as lipopoly- Graduate School of Biomedical Sciences at Houston, Houston,Texas saccharide), two kinases, TGFh-activated kinase 1 (TAK1) and Received 4/8/08; revised 5/16/08; accepted 5/20/08. Grant support: NIH grants R01CA109311and P01CA099031, grants from the mitogen-activated protein/ERK kinase kinase 3, are recruited Kadoorie Charitable Foundation, National Breast Cancer Foundation, Inc., and into the proximity of the IKK complex by interacting with Breast Cancer Research Foundation (M-C. Hung). A predoctoral fellowship from several receptor-associated proteins, such as receptor-interacting the U.S. Army Breast Cancer Research Program (grant W81XWH-05-1-0252); serine-threonine kinase 1, thereby phosphorylating and acti- scholarships from theT. C. Hsu Endowed Memorial Scholarship Fund, the Andrew vating both IKKa and IKKh in the cytoplasm. A major Sowell-Wade Huggins Endowed Scholarship Fund, and the Presidents’ Research h Scholarship Fund from The University of Texas Graduate School of Biomedical consequence of IKKa/IKK activation is the initiation of Sciences at Houston (D-F. Lee). NF-nB–mediated transcriptional activation. Although these Requests for reprints: Mien-Chie Hung, Department of Molecular and Cellular two kinases have a high degree of structural similarity and are Oncology, Unit 108,The University of Texas M. D. Anderson Cancer Center, 1515 both present in the classic IKK complex, their downstream Holcombe Boulevard, Houston,TX 77030. Phone: 713-792-3668; Fax: 713-794- 3270; E-mail: [email protected]. substrates and physiologic functions can be quite different. In F 2008 American Association for Cancer Research. fact, both IKKa and IKKh have recently been shown to function doi:10.1158/1078-0432.CCR-08-0123 independently of each other and to have nonoverlapping

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Fig. 1. The canonical and noncanonical NF-nB signaling pathways. The canonical pathway is critical for the activation of innate immunity and inflammation (left). It is activated by TNFa, IL-1, and lipopolysaccharide. Activation of this pathway depends on the IKKa/IKKh/ IKKg complex, which phosphorylates InB proteins to trigger their degradation through h-TrCP ubiquitin proteasome. The noncanonical pathway is crucial for the activation of adaptive immunity (right). It is acti vated by lipopolysaccharide, B cell ^ activating factor of theTNF family, and latent membrane protein 1. Activation of this pathway depends on IKKa homodimers which phosphorylate p100 to induce p100/RELB heterodimers processing intop52/RELB heterodimers.

functions. This functional difference will be discussed further in suppressor Maspin (7), which is a serpin peptidase inhibitor this review (see below). Unlike IKKa and IKKh, which are that blocks tumor metastasis. Also, IKKq and TBK1 prevent major catalysts of the NF-nB pathway, IKKq and TBK1 have cancer cell apoptosis through the NF-nB and RalB/Sec5 restricted functions in the NF-nB activation pathway. They pathways, respectively (8, 9). Before the targeting of IKK and are activated by toll-like receptor agonists and viral ssRNA in IKK-related kinases becomes a viable therapeutic intervention the cytoplasm and mainly function as mediators of type IIFN for cancer, a better understanding of their respective functions gene expression, which contributes to the antiviral response in broad-spectrum signaling transduction and gene expression by their activation of the IFN regulatory transcription factors 3 is necessary (Fig. 2). and 7 (IRF3 and IRF7), which are transcriptional factors with Consequences of IKKb activation. IKKh is one component of diverse roles in immunity and cellular response to viral infec- the classic IKK complex, which is composed of three subunits, tions. Thus, IKKq and TBK1 are important mediators of anti- two catalytic kinases (IKKa and IKKh), and a regulatory scaffold viral response and, together with IKKa and IKKh, coordinate component IKKg. Upon stimulation by either TNFa or IL-1h, and organize the host immune defense. activated IKKh phosphorylates the NF-nB inhibitor InBa and Consequences of IKK activation in human cancer. Because of subsequently triggers its rapid degradation through the h- their importance in regulating the expression of proinflamma- TrCP–derived ubiquitin-proteasome pathway, which liberates tory cytokines and chemokines, angiogenic factors, antiapop- the NF-nB heterodimer from InBa. No longer inhibited by totic proteins, cell adhesion molecules, and enzymes, IKK and InBa, the NF-nB heterodimer translocates to the nucleus from IKK-related kinases are believed to function as oncogenic the cytoplasm, binds to its target DNA sequence, and induces kinases (4, 5). For instance, IKKh functions as an oncoprotein the expression of a myriad of genes involved in immune in breast cancer by promoting the degradation of forkhead response (TNFa, IL-1, MCP-1, and COX2), cell proliferation box O3a (FOXO3a; ref. 6), which is a forkhead transcriptional (cyclin D1, cyclin D2, c-MYC, and JUNB), angiogenesis factor that functions in both the inhibition of the cell cycle (vascular endothelial growth factor, IL-6, and IL-8), cell and the promotion of cell apoptosis, and IKKa serves as a survival (XIAP, BCL-xL, c-IAP2, and GADD45h), invasion and tumor metastasis promoter by down-regulating the tumor metastasis (matrix metalloproteinase-9 and urokinase-type

www.aacrjournals.org 5657 Clin Cancer Res 2008;14(18) September 15, 2008 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2008 American Association for Cancer Research. Molecular Pathways plasminogen activator), and epithelial-mesenchymal transition complex with mitogen-activated protein kinase kinase kinase (TWIST and SNAIL; ref. 10). Because a variety of NF-nB target 8 (MAP3K8, also known as Tpl2 and Cot). IKKh-induced genes function as hallmarks that are required for cancer phosphorylation of p105 NF-nB leads to its degradation, which development, the biological consequence of IKKh activation activates MAP3K8, and the activated MAPK8 then activates the is tumor progression. MAPK pathway, which increases cell proliferation (12, 13). Although its function as an IKK is scientific dogma, IKKh IKKh might also affect the MAPK pathway by phosphorylation- does more than simply induce InB degradation and, conse- mediated suppression of the ras-GTPase–activating protein– quently, NF-nB activation. Recently, many of the non-InB associated tyrosine kinase substrate DOK1 (14), which is a targets of IKKh have been identified, suggesting that IKKh docking protein involved in the inhibition of the MAPK path- programs the widespread cellular response to extracellular way, cell migration, and cell proliferation (15–17). IKKh- stimulation and effects on cell signaling that were previously mediated DOK1 phosphorylation relieves DOK1-mediated unsought. In addition to phosphorylating InB proteins to repression of cell migration and spreading, which may con- activate the NF-nB signaling axis, IKKh can directly phosphor- tribute to TNFa-induced cell metastasis. ylate RELA, a transcriptional factor binding to p50 NF-nB1 As mentioned above, IKKh-mediated FOXO3a phosphoryla- to form a heterodimer which is the most abundant form of tion induces its nuclear exclusion and ubiquitination, and the NF-nB. IKKh-mediated RELA phosphorylation not only induces expression of IKKh is correlated with cytoplasmic FOXO3a in RELA nuclear translocation but also promotes its interaction multiple human cancers (6), indicating that the regulation with a transcriptional coactivator to enhance its transactivation of FOXO3a phosphorylation by IKKh is significant in cancer (11). Additionally, p105 NF-nB has been found to form a development. Consistent with its role in NF-nB–mediated

Fig. 2. IKK and IKK-related kinases induce the phosphorylation of their downstream substrates, leading to their activation (yellow) or inhibition (orange). Regulation of these substrates by IKKa,IKKh,IKKq, and TBK1has been shown to contribute to tumor development by increasing tumor angiogenesis and metastasis, promoting cell proliferation, and generating resistance to cell apoptosis. See text for a detailed description of downstream inhibitory or activation substrates of IKK and IKK-related kinases.

ClinCancerRes2008;14(18)September15,2008 5658 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2008 American Association for Cancer Research. IKK and IKK-Related Kinases in Cancer Development vascular formation via vascular endothelial growth factors interacts with the cyclic AMP–responsive element binding (VEGF-A and VEGF-C), IKKh has been shown to phosphorylate protein (CREB)-binding protein (CBP), and phosphorylates tuberous sclerosis 1 (TSC1), a peripheral membrane protein histone H3 at serine 10. The regulation of histone H3 phos- known to be associated with the development of tuberous phorylation by IKKa is critical for the activation of a subset of sclerosis, and inhibit its tumor suppressor function, which NF-nB–dependent genes induced by inflammatory cytokines increases tumor angiogenesis (18, 19). IKKh-induced TSC1 (29, 30). In addition to binding with CBP to regulate histone phosphorylation inhibits its association with GTPase-activating function, IKKa directly phosphorylates CBP and switches its protein (TSC2), alters TSC2 membrane localization, increases binding preference from p53 to NF-nB. IKKa-mediated CBP mTOR activity, enhances vascular endothelial growth factor-A phosphorylation not only facilitates NF-nB–dependent gene expression, and culminates in tumorigenesis. The regulation of expression but also suppresses p53-induced gene transcrip- TSC1 phosphorylation by IKKh has been observed in breast tion (31). Interestingly, the nuclear function of IKKa has cancer, in which it was found to be correlated with a poor also been implicated in prostate cancer metastasis by clinical outcome (18, 19). IKKh has been found to regulate inhibiting the expression of the tumor suppressor Maspin TNFa-mediated TRAF2 ubiquitination and activation of down- (7). It would be interesting to know if along with its stream signaling events via phosphorylation of the tumor function as a switch controlling both NF-nB and p53 sign- suppressor cylindromatosis (20), which is a deubiquitinating aling events (31), IKKa also functions as a suppressor of enzyme mutated in familial cylindromatosis (21). Phosphor- p53-mediated Maspin expression via its regulation of CBP ylation of cylindromatosis by IKKh relieves cylindromatosis- phosphorylation (32). mediated suppression of TRAF2 ubiquitination and induces Consequences of TBK1 activation. TBK1, also called the TNF NF-nB activation (20). receptor–associated factor 2 (TRAF2)–associated kinase (33) Consequences of IKKa activation. IKKa (also known as a or NF-nB–activating kinase (34), is one of two noncanonical conserved helix-loop-helix ubiquitous kinase) is the other IKKs implicated in regulating the activation of IRF3 and NF-nB catalytic kinase of the classic IKK complex. In contrast to signaling pathways (35). Although TBK1 is structurally similar IKKh’s effect on InB phosphorylation in the canonical pathway, to IKKa and IKKh, it is not part of the classic IKKa/IKKh/IKKg IKKa might have a crucial function to facilitate NF-nB– complex, hence, it fails to induce InB degradation. TBK1-null dependent gene transcription instead of InB phosphorylation cells have been shown to have normal InB degradation and due to its lower ability to induce InB phosphorylation. In NF-nB DNA binding but a dramatic reduction in NF-nB– addition, the B cell–activating factor of the TNF family has dependent gene transcription, suggesting that, unlike IKKh been found to induce BAFF receptor engagement and NF-nB participating in InB degradation, TBK1 has a unique role in p52 precursor p100 processing through activation of the IKKa NF-nB activation (33). However, other studies with TBK1 and homodimer, thus mediating the so-called noncanonical IKK IKKq single-null and double-null mice did not confirm a pathway. Activated IKKa-mediated p100 phosphorylation deficiency in NF-nB activation (36, 37). Therefore, the actual gradually causes partial proteolytic degradation of the COOH- role of TBK1 in NF-nB activation needs more investigation. terminal ankyrin repeat region of p100 by h-TrCP ubiquitin- Although the role of TBK1 in the NF-nB pathway remains proteasome processing, which leads to the activation and controversial, its role in regulating the function of IRF3 in nuclear translocation of the p52/RELB heterodimer, and response to viral infection has been well recognized. TBK1 consequently, the induction of cyclin D1 expression. IKKa also coordinates with IKKq to phosphorylate IRF3 and IRF7, and regulates cyclin D1 expression via a number of p52/RELB- therefore induces their activation and nuclear translocation independent mechanisms. For instance, IKKa phosphorylates to drive IFN-h and chemokine RANTES expression (35–37). h-Catenin, which is an oncogenic transcriptional factor Using a genome-wide phenotype screen, Korherr et al. identified responsible for the development of several types of cancers. TBK1 as a ‘‘trigger’’ of the proangiogenic TBK1/IRF3 pathway and IKKa-mediated h-Catenin phosphorylation inhibits h-Catenin found that it was overexpressed in breast and colon cancers (38). ubiquitination and degradation, and stimulates h-Catenin/T- Thus, TBK1-mediated tumor angiogenesis may occur through cell factor–dependent cyclin D1 expression, which enhances the IRF3-driven expression of several angiogenic factors, which tumor proliferation (22–25). results in tumor progression. Using a chemical proteomic In addition to h-Catenin, IKKa phosphorylates both the approach, Godl et al. characterized TBK1 as a novel target of estrogen receptor-a transcriptional factor and the estrogen the angiogenesis inhibitor SU6668 (39), which further empha- receptor-a coactivator protein AIB1/SRC3 and activates estro- sizes the proangiogenic role of the TBK1/IRF3 signaling axis in gen receptor-a downstream targets such as cyclin D1 and cancer development. TBK1 has also been shown to be involved c-MYC, thereby promoting cell proliferation in breast cancer in the monomeric RalB GTPase-mediated innate immune (26, 27). The suggestion that IKKa directly phosphorylates signaling response and in tumor cell survival (9). TBK1 is cyclin D1 and promotes cyclin D1 degradation remains con- activated by the RalB/Sec5 effector complex, and activation of the troversial (28). Based on these findings, the current model RalB/Sec5/TBK1 pathway restricts tumor cell apoptosis induced implicated that IKKa-mediated cyclin D1 down-regulation may by oncogenic stress (9). In contrast to its oncogenic role in a serve as a feedback regulator in the suppression of IKKa- variety of human malignancies, TBK1 has been shown to be induced cell growth. Recently, several studies have discovered responsible for the antitumor activity of the chemotherapeutic and examined the novel function of nuclear IKKa and have agent 5,6-dimethylxanthenone-4-acetic acid, which is a small implicated it in tumor progression. IKKa has been found to molecule in the flavanoid class functioning as a vascular mediate NF-nB downstream gene expression by modulating the disrupting agent currently under investigation in phase II clinical chromatin structure. Upon activation by TNFa stimulation, trials. 5,6-Dimethylxanthenone-4-acetic acid has been shown to IKKa shuttles from the cytoplasm to the nucleus, where it robustly induce TBK1/IRF3-mediated IFN-h expression in

www.aacrjournals.org 5659 Clin Cancer Res 2008;14(18) September 15, 2008 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2008 American Association for Cancer Research. Molecular Pathways primary murine macrophages, which is indicative of its Compared with its inhibitory effect on IKKh, SPC-839 only antitumor activity (40, 41). weakly inhibits IKKa (IC50 =13Amol/L). It suppresses NF-nB– Consequences of IKKe activation. IKKq (also called IKK-i) is mediated IL-6 and IL-8 production in Jurkat T cells (48). the other noncanonical IKK involved in regulating the ML120B (Millennium Pharmaceuticals, Inc.). A h-carboline activation of the IRF3 and NF-nB signaling pathways (35). compound reported to be a selective, reversible, and ATP- Upon activation in response to toll-like receptor agonists and competitive inhibitor of IKKh (IC50 = 50 nmol/L). It has q viral infection, IKK phosphorylates IRF3 and IRF7 and triggers little effect on other cellular kinases, including IKKa (IC50 > IRF3/IRF7 nuclear translocation, which results in the up- 100 Amol/L) and IKKq (IC50 > 100 Amol/L). ML120B blocks regulation of type I IFN expressions. It has been suggested that TNFa-derived InBa phosphorylation and NF-nB transcriptional IKKq is involved in TNFa-induced and lipopolysaccharide- activity. It also interferes with TNFa– and IL-1h–induced IL-6, induced matrix metalloproteinase-3 and matrix metalloprotei- RANTES, and MCP-1 expression (49). nase-13 gene expressions via phosphorylation and activation of SC-514. An aminothiophenecarboxamide derivative that has the c-JUN transcriptional factor (42). IKKq-mediated c-JUN been identified as a selective, reversible, and ATP-competitive phosphorylation might be responsible for synovial inflamma- inhibitor of IKKh (IC50 = 6.5-15.9 Amol/L). However, it does not tion and extracellular matrix destruction in rheumatoid arthritis inhibit other IKK family members [IKKa (IC50 > 200 Amol/L), as well as being involved in tumor invasion and metastasis. Like IKKq (IC50 > 200 Amol/L), and TBK1 (IC50 > 200 Amol/L)] IKKh,IKKq phosphorylates InBa at Ser32 and Ser36 (preferen- and has little effect on other cellular protein kinases. It blocks tially at Ser36) and stimulates NF-nB activation (43). Using IL-1h–induced IL-6 and IL-8 production via the inhibition of three integrative genetic approaches, Boehm et al. identified IKKh-mediated InBa phosphorylation and degradation, and IKKq as an oncogene in human breast cancer. Abnormal up- the partial interference of NF-nB nuclear translocation (50). n q regulation of NF- B activity by IKK is an essential step for cell However, its short half-life (t1/2 = 12 minutes) and limited transformation induced by AKT, indicating that IKKq acts bioavailability (2%) may restrict its clinical application. downstream of AKT and links the phosphoinositide-3-kinase CHS828. A pyridyl cyanoguanidine derivative that has and NF-nB pathways (8). Whole genome structural analyses shown a significant antitumor effect in in vivo and in vitro disclosed that IKKq is amplified and overexpressed in human studies and is currently being evaluated in phase I/II clinical breast cancers and that knockdown of IKKq promotes apoptosis trials (51). It impairs lipopolysaccharide-mediated NF-nB in breast cancer cells (8), suggesting that a mechanism for NF- nuclear translocation and transcriptional activation via the n q B activation is involved in IKK -mediated breast cancer inhibition of IKK activities (IC50 = 8.0 nmol/L). In addition, development. one of its analogues, CHS850, exhibits a similar ability to inhibit IKK-mediated NF-nB activation (IC50 = 6.5 nmol/L; Clinical-Translational Advances ref. 52). SU6668 (Sugen, Inc.). An antiangiogenic small-molecule Many pharmaceutical companies are developing increasingly drug (which has completed phase Iclinical trials) that is a smaller molecular protease inhibitors that target IKK and IKK- receptor tyrosine kinase inhibitor. It is an indolinone com- related kinases. Most of these small-molecule inhibitors target pound that has been characterized as an ATP-competitive IKKh because it is the major player in the NF-nB pathway. Although most IKK inhibitors being developed are still in the inhibitor of vascular endothelial growth factor receptor 2, preclinical stage of testing, some have been well characterized platelet-derived growth factor receptor, and fibroblast growth and have shown promising inhibitory effects in either in vitro or factor receptor (53). Recently, it was found to block TBK1 A in vivo studies. In addition to using specific small-molecule activity (IC50 =5.2 mol/L) and to inhibit TBK1-mediated IRF3 inhibitors to target IKK and IKK-related kinases, researchers activation and IFN-h production (39). are also investigating other targeting strategies via the use of RNA interference and small interfering RNAs. A promising macromolecules, including genes, oligonucleotides, and pep- therapeutic approach for cancer treatment that uses antisense tides. We briefly describe these advances in targeting IKK and oligonucleotides to directly target the nucleic acid sequence of IKK-related kinases here and summarize them in Table 1. IKKa,IKKh,IKKq, and TBK1 (54). These antisense oligonucleo- PS-1145 (Aventis Research and Technologies/Millennium tides can be delivered to tumors via liposomes or nanoparticles. Pharmaceuticals, Inc.). A h-carboline natural product deriva- Gene therapy. An attractive therapeutic intervention for tive that has been shown to be an IKKh inhibitor (IC50 = cancer that uses DNA vectors encoding therapeutic genes to 150 nmol/L). It suppresses TNFa-mediated InB phosphoryla- target cancer cells. Ideally, it can be systemically delivered to tion and degradation, inhibits NF-nB activation (44), and any type of tumor, including solid tumors, micrometastatic induces multiple myeloma cell toxicity in the presence of tumors, and cancer cells in the bloodstream. Adenovirus type 5 TNFa (45). E1A has been found to inhibit TNFa-induced InBa degradation BMS-345541. A small-molecule drug that targets an allo- and NF-nB activation via suppression of IKKh activity (55). It steric site of IKKh (IC50 =0.3Amol/L) and of IKKa (IC50 = has also been shown to inhibit radiation-induced NF-nB 4 Amol/L) but has little effect on 15 other cellular kinases. activation and to sensitize cells to TNFa-induced apoptosis It blocks lipopolysaccharide-stimulated TNFa, IL-1h, IL-6, and in multiple types of cancer (56). Multiple clinical trials have IL-8 production with IC50 in the range of 1 to 5 Amol/L in vitro been completed and a phase I/II trial of E1A-paclitaxel (46). No toxicologic changes were observed in mice treated combination therapy in patients with ovarian cancer is cur- with BMS-345541 (at a daily dose of 100 mg/kg for 6 weeks; rently under way at the University of Texas M. D. Anderson ref. 47). Cancer Center (57–60). SPC-839 (Celgene Corporation). A quinazoline analogue Cell-permeable peptides. The NH2-terminal a-helical region that has been developed to target IKKh (IC50 = 67 nmol/L). of IKKg has been found to be associated with the COOH-

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Table 1. Summary of targeting strategies to inhibit IKK activity

Strategies Potential targets Therapeutic agents References Small molecule inhibitors IKKa/h PS-1145 Castro et al. (44),Hideshima et al. (45) BMS-345541 Burke et al. (46),Mclntyre et al. (47) SPC-839 Palanki et al. (48) CHS828 Hiarnaa et al. (51),Olsen et al. (52) IKKh ML120B Wen et al. (49) SC-514 Kishore et al. (50) TBK1 SU6668 Godl et al. (39) RNA interference and small interfering RNAs IKKa/h/q and TBK1 Takaesu et al. (54) Gene therapy IKKh E1A Shao et al. (55,56) Cell-permeable peptides IKKa/h/g complex IKKh[644-756] peptide May et al. (61)

terminal region of IKKh. Based on the concept of competition, Several small-molecule IKK inhibitors and other strategies the use of cell-permeable peptides that block the IKKg-binding targeting IKK and IKK-related kinases have shown significant domain (IKKh[644-756]) to interfere with IKK complex func- results in preclinical studies and some are generating promis- tion has been suggested. In two experimental mouse models ing preliminary results in clinical trials. The hope is that several of acute inflammation, this peptide blocked TNFa-mediated of these small-molecule drugs and/or targeted gene therapies and phorbol 12-myristate 13-acetate–mediated NF-nB activa- will enter future clinical trial tests to help provide a complete tion but did not inhibit the basal NF-nB activity (61). evaluation of the potential for targeting IKK and IKK-related kinases as a therapeutic intervention for cancer. Conclusion

Recent experimental data on the role of IKK and IKK-related Disclosure of Potential Conflicts of Interest kinases suggest that they have critical roles in inflammation- Nopotential conflicts ofinterest were disclosed. mediated human diseases, including many different types of cancer. IKK and IKK-related kinases promote cancer develop- Acknowledgments ment in humans not only through the up-regulation of the expression of NF-nB and IRF downstream targets but also We thank Hsu-Ping Kuoand Adam M. LaBaff forhelpful discussions, and Lionel through the interruption of multiple cellular protein functions. Santiban˜ez of the Department of Scientific Publications for his editorial assistance.

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Dung-Fang Lee and Mien-Chie Hung

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