X-Linked Inhibitor of Apoptosis Antagonism: Strategies in Cancer Treatment Herman H

Molecular Pathways

X-Linked Inhibitor of Apoptosis Antagonism: Strategies in Cancer Treatment Herman H. Cheung,1Eric C. LaCasse,2 and Robert G. Korneluk1, 2

Background conserved RING and baculovirus IAP repeat (BIR) zinc finger domains, all under the translational control of a stress- X-linked inhibitor of apoptosis (XIAP), first identified in regulated internal ribosome entry site (7). The antiapoptotic 1996 (1), is a member of the IAP family of endogenous caspase property of XIAP has been attributed to direct inhibition and inhibitors that blocks the execution of apoptosis. The inhibi- proteasome-dependent degradation of caspases, as well as the tory function of XIAP can be reversed by its antagonists, activation nuclear factor-nB signaling pathways. Although XIAP whereas its abundance can be regulated in a proteasome- was initially described as an activator of c-Jun NH2-terminal dependent manner. In less than a decade, great strides made in kinase survival pathway, it was subsequently found that understanding basic XIAP function has translated into clinical depending on cell type and the initial signal, XIAP may either research targeting this IAP in cancer malignancy (2). activate or repress c-Jun NH2-terminal kinase activation (8, 9). XIAP protein possesses three characteristic NH2-terminal 70- to Apoptosis pathways and XIAP 80-amino-acid BIR domains and a COOH-terminal RING zinc Apoptosis is controlled by the activation of a zymogen finger domain. BIR1 of XIAP contains an Akt phosphorylation caspase cascade and the inhibition of the resulting active site at residue Ser87 that is involved in protein stabilization proteases (3). Initiation of apoptosis occurs by signals from (10). The anti-caspase activities of XIAP can be ascribed to BIR two distinct but convergent pathways: the extrinsic death domains and their linker regions: BIR3 is an inhibitor to the receptor pathway and intrinsic mitochondrial apoptosome initiator caspase-9 and the linker preceding BIR2 functions as pathway (Fig. 1). These two pathways consist of largely distinct an inhibitor to effector caspase-3 and caspase-7 (6). The molecular interactions and use different upstream, initiator COOH-terminal RING domain of XIAP is an E3 ubiquitin caspases that are often interconnected at numerous steps to ligase capable of recruiting target proteins to a complex ultimately converge at the level of downstream effector caspase containing an E2 enzyme for ubiquitin-conjugation and activation (4). As the only known endogenous proteins that proteasomal degradation (11). XIAP can trigger the ubiquiti- function as direct, physiologic repressors of both initiator and nation of caspase-3 and caspase-7 (12, 13), suggesting that effector caspases (5, 6), the IAPs play a pivotal role in the targeting of caspases to the proteasome may be another regulation of the apoptotic cascade, representing an important antiapoptotic mechanisms of the IAPs. Interestingly, E3 survival factor in cancer cells. autoubiquitination function of XIAP can be turned on by the XIAP (hILP/birc4) is arguably the most potent IAP with binding of antagonists, such as Smac3, a splice variant of Smac respect to its antiapoptotic functions; therefore, it is not with exon 4 deleted (14). surprising that XIAP is also one of the better studied and understood IAPs. XIAP is a multifaceted molecule composed of XIAP and cancer: regulation, antagonists, and proteasome XIAP is frequently overexpressed in NCI 60 cell line panel of Authors’ Affiliations: 1Apoptosis Research Centre, Children’s Hospital ofEastern cancer cells and in cancer tissues compared with normal tissues Ontario, Research Institute, Ottawa, Ontario, Canada and 2AegeraTherapeutics, Inc., (15, 16). Notably, a strong positive correlation exists between Montreal, Quebec, Canada the levels of XIAP and caspase-3 in breast, colon, and pancreatic Received 4/5/06; accepted 4/10/06. cancers (17, 18), suggesting that the down-regulation of XIAP Grant support: Our research in the IAP field is supported by Canadian Institutes ofHealth Research, Howard Hughes Medical Institute, Ontario Research might release caspase-3 inhibition and promote the execution and Development Challenge Fund, Canadian Genetic Diseases Network, of apoptosis in cancer cells. Muscular Dystrophy Canada, Muscular Dystrophy Association USA, and Aegera The therapeutic potential of XIAP suppression in cancer Therapeutics, Inc. treatment has encouraged research into identifying and Note: Presented at the AACR-National Cancer Institute-European Organization for Research and Treatment ofCancer International Conference on MolecularTargets characterizing mechanisms that regulate XIAP abundance as and CancerTherapeutics: Discovery, Biology, and Clinical Applications, November well as antagonists that block XIAP functions. In addition to the 14 to 18, 2005, Philadelphia, Pennsylvania. E3 ligase of XIAP promoting its own destruction (19), H.H. Cheung is the recipient ofa Michael Cuccione Foundation and the Canadian proteasome-dependent degradation of XIAP can be mediated Institutes ofHealth Research Institute ofCancer Research postdoctoral fellowship. by E3 ligases of other IAPs, such as cIAP1 and cIAP2 (20). R.G. Korneluk is a Howard Hughes Medical Institute International Research Scholar and a Fellow ofthe Royal Society ofCanada. Conversely, formation of another IAP-XIAP complex, involving H.H. Cheung and E.C. LaCasse contributed equally to this work. survivin that lacks a E3 ligase RING domain, promotes We apologize to those whose studies were not cited due to space limitations. increased XIAP stability against proteasome-mediated degrada- Requests for reprints: Robert G. Korneluk, Department ofPediatrics, Children’s tion and synergistic inhibition of apoptosis (21). Moreover, Hospital ofEastern Ontario, Ottawa, Ontario K1H 8L1, Canada. P hone: 613-738- upon phosphorylation at Ser87,XIAPisprotectedfrom 3281;Fax: 613-738-4833; E-mail: [email protected]. F 2006 American Association for Cancer Research. ubiquitination and degradation in response to the chemother- doi:10.1158/1078-0432.CCR-06-0817 apeutic agent cisplatin (10).

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The caspase inhibition function of the BIR domains can be specific drugs to target XIAP mRNA and induce their reversed by negative regulators, primarily mitochondrial degradation through RnaseH or RISC complexes. Relatively apoptogenic factors, such as Smac/DIABLO (22, 23) and soon after the discovery of XIAP, functional studies showed possibly Omi/HtrA2 (24), but also other factors, such as that overexpression of this IAP was highly cytoprotective cytoplasmic/endoplasmic reticulum protein eRF3 (25) and (29). The converse, however, that XIAP down-regulation in a the candidate tumor suppressor XIAP-associated factor 1 (26). cancer cell would lead either to outright cell death, or at the Caspase activation as a result of displacement from XIAP by least, sensitization to apoptosis induction by cytotoxic agents, Smac, Omi, and eER3 is mediated by the IAP-binding motif, took many more years to firmly establish. This question has a conserved tetrapeptide sequence (e.g., AVPI) exposed at the been positively answered, initially with full-length antisense NH2 terminus after proteolytic cleavage (22, 23). Smac was the followed by antisense oligonucleotides, then short hairpin earliest identified XIAP antagonist and has become the basis RNA or small interfering RNA vectors, and most recently, by for many studies that examine the potential of suppressing other gene ablation ‘‘knock-out’’ approaches (2). For exam- XIAP in cancer treatment. Recent studies have reported that ple, a recent publication by Ravi et al. (30) shows that small-molecule mimics of Smac are effective agents in relieving HCT116 human colon carcinoma xenografts lacking XIAP are XIAP-mediated suppression of caspase activity to promote the highly sensitive to immune attack in mice compared with cells regression of established tumors in xenograft models in mice either containing XIAP or lacking other apoptotic pathway (27, 28). genes. Advances in second-generation chemistry have made anti- Clinical-Translational Advances sense a tractable route to therapeutic development. Indeed, a XIAP antisense compound (AEG35156) has been in the clinic The on-going validation of XIAP as a genuine anticancer for the past 2 years (2). The much anticipated results from these target has been paralleled by strategies that aim to antagonize and future trials will establish if XIAP is a bona fide drug target, this IAP (Fig. 2). These different approaches are in various or not, and perhaps lead the way forward to the development of stages of development, from preclinical to a phase I clinical novel small-molecule anti-XIAP compounds. trial. A brief detailing of these efforts offers us a glimpse of what Inhibitors of translation. XIAP protein levels are primarily can be anticipated in the coming years. influenced through translation control and protein stability, Inducers of mRNA degradation. Currently, the sole strategy mediated by the ubiquitin-proteasome pathways. The XIAP being evaluated in the clinic is with AEG35156, a second- mRNA transcript is quite stable, almost ubiquitous and generation antisense targeting the coding region of XIAP (2). unchanging. Thus, one strategic approach is to develop Antisense or RNA interference approaches allow the design of inhibitors of XIAP translation to block the expression of XIAP

Fig. 1. XIAP is central to the regulation of apoptosis. Pathways triggered by death receptor (e.g., tumor necrosis factor ^ related apoptosis-inducing ligand mediated) and mitochondria-mediated pathway converge at the execution phase ofapoptosis.The caspase-binding and caspase-inhibiting activity ofXIAP resides in the NH 2-terminal BIR domains that specifically binds and inhibits the initiator caspase-9 as well as the effector caspase-3.The anti-caspase activity ofXIAP can be blocked by Smac/DIABLO (and also Omi and XAF1). The E3 ubiquitin ligase activity ofXIAP is involved in autoubiquitination and self-destruction as well as the removal ofcaspase-3 and Smac.

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Fig. 2. Targeted approaches to chemical antagonism ofXIAP. *, only compound under clinical investigation. **, polyphenylurea compounds, such asTPI-1396-11(43), TPI-139 6-12 (37, 4 4), TPI-139 6-34 (36, 44), andTPI-1540-14 (45). ***, aryl sulfonamides, such asTWX006, TWX024, andTWX041 (46).****, SMAC peptidomimetics, such as compound 3 (27), IDN13389 (28), NSC321206 (47), GT12726 (48), SH122and other unnamed compounds (49, 50). AAAA, polyadenylated tail; ATG, start codon; FADD, Fas-associated death domain; IRES, internal ribosome entry site; RING,RINGzincfingerdomain;siRNA,small interfering RNA; UTR, untranslated region. Gold, oligonucleotide chemistries. Green, traditional synthetic or natural product small molecule compounds. Adapted in part from the following references: (51 ^ 56).

in cancer cells under stress. This approach has merit, as searches (38). Cocrystal structures of XIAP and Smac revealed that for inhibitors of the Hepatitis C viral internal ribosome entry a simple IAP-binding motif of four NH2-terminal amino site continue, although without success to date. A greater acid residues, AVPI, was sufficient to bind to a conserved understanding of these internal ribosome entry site–based groove on XIAP BIR3, a site that was also shown to be translational control mechanisms is needed to identify truly important for caspase-9 inhibition (39). Simple tetrapeptides tractable targets. Nonetheless, a recent report by Yan et al. (31) consisting of natural or non-natural amino acids, built around identify the mammalian target of rapamycin inhibitor rapamy- this IAP-binding motif sequence, were capable of displacing cin as preferentially and significantly inhibiting the translation caspase-9 from XIAP and of activating the caspase cascade (27), of XIAP as substantiated by a decreased polysomal association a finding that provided the rationale for the design of small- of the XIAP mRNA. Such studies hold promise that specific and molecule peptidomimetics as specific drug candidates. This useful small-molecule inhibitors can be found. An alternative class of Smac mimetics has drawn the most interest thus far, to the small-molecule approach is the use of a morpholino with many development efforts under way (27, 28). It remains antisense oligonucleotide targeting the ATG (32) or a second- to be proven if compounds that selectively disrupt protein- generation antisense targeting the region just upstream of the protein interactions can translate successfully to the clinic and ATG (33). In addition, small interfering RNA targeting the 3¶ then to the market. However, advances being made with other untranslated region can potentially interfere with translation or disruptor compounds, such as Nutlin-3 that targets p53-MDM2 deadenylate and destabilize the message (34, 35). interaction (40), however, offer promise that such approaches Disruptors of caspase-3 binding. Because the major anti- are viable. apoptotic action of XIAP is through inhibition of caspase-3 and Destabilizers of XIAP protein half-life. The various Akt kinase caspase-7 (via the BIR1-2 linker) and caspase-9 (via BIR3), inhibitors under development may derive their benefit in part chemical screen of compounds that disrupt the interaction by destabilizing XIAP, leaving the hypophosphorylated XIAP between caspase-3 and XIAP have been undertaken. One such protein more susceptible to ubiquitination-mediated degrada- approach has led to the identification of a novel class of tion (10). Alternatively, compounds that directly modulate the polyphenylurea compounds that antagonizes the ability of ubiquitin-proteasomal pathways may be useful, although it is XIAP to inhibit caspase-3 (36, 37). The best candidates in this unclear how E3 ligase inhibitors, for example, may affect cancer class (e.g., antagonist 1396-34; ref. 36) show a good therapeutic cell viability. Presumably, they would block the antiapoptotic index with apoptosis induction in a select group of cancer cell action of XIAP RING domain that would function to lines. Furthermore, antitumor effects in vivo have been shown ubiquinate key targets, such as caspase-3 and Smac, and (36). Although therapeutic compounds that disrupt protein- potentially also destroy the ability of the cell to remove XIAP protein interactions may never, in fact, translate to the clinic, when cell death is induced. Nevertheless, the identification and they represent important proof-of-concept for the testing of characterization of E3 ligase inhibitors remains crucial to the many important questions regarding XIAP function, biology, understanding of apoptosis inhibition in cancer and to the and antagonism. development of novel therapeutic strategies aimed at overcom- Disruptors of caspase-9 binding (Smac peptidomimetics). The ing apoptotic resistance. discovery of the second mitochondrial activator of caspases, Nonspecific inhibitors: XIAP loss, cause, or consequence? All Smac/DIABLO (the first activator being cytochrome c)asan compounds that claim to be XIAP antagonists are not antagonist of XIAP showed the importance of this particular necessarily direct XIAP inhibitors. For example, phenoxodiol pathway in programmed cell death (22, 23). Smac is also the may represent one such compound (41) for which no evidence ‘‘competence to die’’ factor required for the death of post- exists for a specific mechanism of XIAP antagonism. Like so mitotic cells for which cytochrome c, by itself, is insufficient many other cytotoxic compounds, phenoxodiol treatment of

cancer cells results in the loss of XIAP protein. Thus, it is therapy may be envisaged in the future, for which we are only difficult to discern if phenoxodiol treatment results in the direct just beginning to understand. loss of XIAP or if XIAP protein reduction is an indirect consequence of death. Most likely, the effects of these The Path Forward nonspecific inhibitors of XIAP are mediated through some other targets or pathways that ultimately trigger cell death and Over the last decade, numerous studies have revealed that the degradation of XIAP. XIAP is a central regulator of caspase activity and a crucial factor Gene therapy, peptide, and protein therapy. Other forms of in the execution of cell death. Various strategies are under therapy, different than small molecules and antisense oligonu- development seeking to take advantage of the key role of XIAP cleotides, may be available in the future. These forms would in programmed cell death. First and foremost, the current include gene therapy approaches at delivering XIAP antagonists, approach using XIAP antisense has offered an informative and such as Smac or XIAP-associated factor 1, to tumor cells. quick route to the clinic. Hopefully, these initial trials will usher Peptide or protein therapy approaches using transducing in a new era of therapeutics aimed at inducing cell death in a constructs involving AVPI or processed Smac polypeptides malignant population of cells while sparing normal cells. These have already shown merit in preclinical models of cancer. For and other specific XIAP antagonists could be used alone, or in example, mice bearing gliomas in the central nervous system combination with a conventional chemotherapy or radiother- were cured with a coadministration of Tat-Smac peptides and apy. Clearly, we will enhance our understanding of cancer tumor necrosis factor–related apoptosis-inducing ligand but treatment in the clinic through the chemical modulation of not by either agent alone (42). Surely, many other forms of XIAP and the associated apoptosis pathways.

References 1. Liston P, Roy N, Tamai K, et al. Suppression ofapo- factor 1 (XAF1) in cancer cell lines. Genomics 2000; itors ofapoptosis (IAPs) and their emerging role in ptosis in mammalian cells by NAIPand a related family 70:113^ 22. cancer. Oncogene 1998;17:3247 ^ 59. ofIAP genes. Nature 1996;379:349 ^ 53. 16. Tamm I, Kornblau SM, Segall H, et al. Expression 30. Ravi R, Fuchs EJ, Jain A, et al. Resistance of 2. Lacasse EC, Kandimalla ER, Winocour P, et al. and prognostic significance of IAP-family genes in cancers to immunologic cytotoxicity and adoptive Application ofXIAP antisense to cancer and other human cancers and myeloid leukemias. Clin Cancer immunotherapy via X-linked inhibitor ofapoptosis proliferative disorders: development of AEG35156/ Res 2000;6:1796^803. protein expression and coexisting defects in mitochon- GEM(R)640. Ann N YAcad Sci 2005;1058:215^ 34. 17. Parton M, Krajewski S, Smith I, et al. Coordinate drial death signaling. Cancer Res 2006;66:1730 ^ 9. 3. Salvesen GS, Abrams JM. Caspase activation: step- expression ofapoptosis-associated proteins in human 31. YanH,FrostP,ShiY,etal.Mechanismbywhich ping on the gas or releasing the brakes? Lessons from breast cancer before and during chemotherapy. Clin mammalian target ofrapamycin inhibitors sensitize humans and flies. Oncogene 2004;23:2774 ^ 84. Cancer Res 2002;8:2100 ^ 8. multiple myeloma cells to dexamethasone-induced 4. Strasser A, O’Connor L, Dixit VM. Apoptosis signal- 18. Yang L, Cao Z, Yan H, et al. Coexistence ofhigh apoptosis. Cancer Res 2006;66:2305 ^ 13. ing. Annu Rev Biochem 2000;69:217^45. levels ofapoptotic signaling and inhibitor ofapopto- 32. Amantana A, London CA, Iversen PL, et al. X-linked 5. Holcik M, Gibson H, Korneluk RG. XIAP: apoptotic sis proteins in human tumor cells: implication for inhibitor ofapoptosis protein inhibition induces apo- brake and promising therapeutic target. Apoptosis cancer specific therapy. Cancer Res 2003;63: ptosis and enhances chemotherapy sensitivity in 2001;6:253 ^ 61. 6815^24. human prostate cancer cells. Mol CancerTher 2004; 6. Liston P, Fong WG, Korneluk RG. The inhibitors of 19. Yang Y, Fang S, Jensen JP, et al. Ubiquitin protein 3:699^707. apoptosis: there is more to life than Bcl2. Oncogene ligase activity ofIAPs and their degradation in protea- 33. Carter BZ, Milella M, Tsao T, et al. Regulation and 2003;22:8568 ^ 80. somes in response to apoptotic stimuli. Science 2000; targeting ofantiapoptotic XIAP in acute myeloid leu- 7. Holcik M, Lefebvre C, Yeh C, et al. A new internal- 288:874^ 7. kemia. Leukemia 2003;17:2081 ^ 9. ribosome-entry-site motifpotentiates XIAP-mediated 20. Silke J, Kratina T, Chu D, et al. Determination ofcell 34. Valencia-Sanchez MA, Liu J, Hannon GJ, et al. cytoprotection. Nat Cell Biol 1999;1:190 ^ 2. survival by RING-mediated regulation ofinhibitor of Control oftranslation and mRNA degradation by miR- 8. Birkey Reffey S,WurthnerJU, ParksWT, et al. X-linked apoptosis (IAP) protein abundance. Proc Natl Acad NAs and siRNAs. Genes Dev 2006;20:515 ^ 24. inhibitor ofapoptosis protein functions as a cofactor Sci U S A 2005;102:16182^ 7. 35. Petersen CP, Bordeleau ME, Pelletier J, et al. Short in transforming growth factor-beta signaling. J Biol 21. Dohi T, Okada K, Xia F, et al. An IAP-IAP complex RNAs repress translation after initiation in mammalian Chem 2001;276:26542 ^ 9. inhibits apoptosis. JBiol Chem 2004;279:34087 ^ 90. cells. Mol Cell 2006;21:533 ^ 42. 9. Kaur S,Wang F,Venkatraman M, et al. X-linked inhib- 22. Du C, Fang M, LiY, et al. Smac, a mitochondrial pro- 36. Schimmer AD, Welsh K, Pinilla C, et al. Small- itor ofapoptosis (XIAP) inhibits c-Jun N-terminal tein that promotes cytochrome c-dependent caspase molecule antagonists ofapoptosis suppressor XIAP kinase 1 (JNK1) activation by transforming growth activation by eliminating IAP inhibition. Cell 2000;102: exhibit broad antitumor activity. Cancer Cell 2004;5: factor beta1 (TGF-beta1) through ubiquitin-mediated 33 ^ 42. 25 ^ 35. proteosomal degradation ofthe TGF-beta1-activated 23.VerhagenAM,EkertPG,PakuschM,etal.Identifica- 37. Carter BZ, Gronda M,Wang Z, et al. Small-molecule kinase1 (TAK1). J Biol Chem 2005;280:38599 ^608. tion ofDIABLO, a mammalian protein that promotes XIAP inhibitors derepress downstream effector cas- 10. DanHC,SunM,KanekoS,etal.Aktphosphoryla- apoptosis by binding to and antagonizing IAP pro- pases and induce apoptosis ofacute myeloid leukemia tion and stabilization ofX-linked inhibitor ofapoptosis teins. Cell 2000;102:43 ^ 53. cells. Blood 2005;105:4043 ^ 50. protein (XIAP). J Biol Chem 2004;279:5405 ^ 12. 24. Suzuki Y, Imai Y, Nakayama H, et al. A serine prote- 38. Deshmukh M, Du C, Wang X, et al. Exogenous 11. Vaux DL, Silke J. IAPs, RINGs and ubiquitylation. Nat ase, HtrA2, is released from the mitochondria and smac induces competence and permits caspase acti- Rev Mol Cell Biol 2005;6:287 ^ 97. interacts with XIAP, inducing cell death. Mol Cell vation in sympathetic neurons. J Neurosci 2002;22: 12. Suzuki Y, Nakabayashi Y,Takahashi R. Ubiquitin- 2001;8:613^ 21. 8018^27. protein ligase activity ofX-linked inhibitor ofapoptosis 25. Hegde R, Srinivasula SM, Datta P, et al. The poly- 39. ShiY.Mechanisms ofcaspase activation and inhibi- proteinpromotesproteasomaldegradationofcaspase- peptide chain-releasing factor GSPT1/eRF3 is proteo- tion during apoptosis. Mol Cell 2002;9:459 ^ 70. 3 and enhances its anti-apoptotic effect in Fas- lytically processed into an IAP-binding protein. J Biol 40.Vassilev LT,Vu BT, Graves B, et al. In vivo activation induced cell death. Proc Natl Acad Sci U S A 2001; Chem 2003;278:38699 ^ 706. ofthe p53 pathway by small-molecule antagonists of 98:8662^7. 26. Liston P, Fong WG, Kelly NL, et al. Identification of MDM2. Science 2004;303:844 ^ 8. 13. MorizaneY, Honda R, Fukami K, et al. X-linked inhib- XAF1as an antagonist ofXIAP anti-caspase activity. 41. Kamsteeg M, Rutherford T, Sapi E, et al. Phenoxo- itor ofapoptosis functions as ubiquitin ligase toward NatCellBiol2001;3:128^33. diolan isoflavone analoginduces apoptosis in mature caspase-9 and cytosolic Smac/DIABLO. 27. Li L, Thomas RM, Suzuki H, et al. A small molecule chemoresistant ovarian cancer cells. Oncogene 2003; J Biochem (Tokyo) 2005;137:125^32. Smac mimic potentiates TRAIL- and TNF{alpha}- 22:2611^ 20. 14. FuJ,JinY,ArendLJ.Smac3,anovelSmac/DIABLO mediated cell death. Science 2004;305:1471 ^ 4. 42. Fulda S,WickW,Weller M, et al. Smac agonists sen- splicing variant, attenuates the stability and apopto- 28. Oost TK, Sun C, Armstrong RC, et al. Discovery of sitize for Apo2L/TRAIL- or anticancer drug-induced sis-inhibiting activity ofX-linked inhibitor ofapoptosis potent antagonists ofthe antiapoptotic protein XIAP apoptosis and induce regression ofmalignant glioma protein. J Biol Chem 2003;278:52660 ^ 72. for the treatment of cancer. J Med Chem 2004;47: in vivo. Nat Med 2002;8:808^15. 15. FongWG,ListonP,Rajcan-SeparovicE,etal. 4417^26. 43. Wang Z, Cuddy M, Samuel T, et al. Cellular, bio- Expression and genetic analysis ofXIAP-associated 29. LaCasse EC, Baird S, Korneluk RG, et al. The inhib- chemical, and genetic analysis ofmechanism ofsmall

www.aacrjournals.org 3241 Clin Cancer Res 2006;12(11) June 1, 2006 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2006 American Association for Cancer Research. Molecular Pathways

molecule IAP inhibitors. J Biol Chem 2004;279: 48. Garber K. New apoptosis drugs face critical test. blockade ofIAP function. J Clin Invest 2005;115: 48168^76. Nat Biotechnol 2005;23:409^11. 2673 ^8. 44. Berezovskaya O, Schimmer AD, Glinskii AB, et al. 49. Sun H, Nikolovska-Coleska Z,Yang CY, et al. Struc- 54. Arkin M. Protein-protein interactions and cancer: Increased expression ofapoptosis inhibitor protein ture-based design, synthesis, and evaluation ofcon- small molecules going in for the kill. Curr Opin Chem XIAP contributes to anoikis resistance ofcirculating formationally constrained mimetics of the second Biol 2005;9:317^ 24. human prostate cancer metastasis precursor cells. mitochondria-derived activator ofcaspase that target 55. Fleischer A, Ghadiri A, Dessauge F, et al. Modulat- Cancer Res 2005;65:2378 ^ 86. the X-linked inhibitor ofapoptosis protein/caspase-9 ing apoptosis as a target for effective therapy. Mol 45. Kater AP, Dicker F, Mangiola M, et al. Inhibitors of interaction site. J Med Chem 2004;47:4147 ^ 50. Immunol 2006;43:1065 ^ 79. XIAP sensitize CD40-activated chronic lymphocytic 50. Sun H, Nikolovska-Coleska Z, Yang CY, et al. 56. Fesik SW.Promotingapoptosis as a strategy forcan- leukemia cells to CD95-mediated apoptosis. Blood Structure-based design ofpotent, conformationally cer drug discovery.Nat Rev Cancer 2005;5:876 ^ 85. 2005;106:1742^ 8. constrained Smac mimetics. J Am Chem Soc 2004; 57. Nikolovska-Coleska Z, Xu L, Hu Z. Discovery of 46.WuTY,Wagner KW, Bursulaya B, et al. Development 126 :1668 6 ^ 7. embelin as a cell-permeable, small-molecular weight and characterization ofnonpeptidic small molecule 51. Schimmer AD, Dalili S, Batey RA, et al. Targeting inhibitor ofXIAP through structure-based computa- inhibitors ofthe XIAP/caspase-3 interaction. Chem XIAP for the treatment of malignancy. Cell Death tional screening ofa traditional herbal medicine three- Biol 2003;10:759 ^ 67. Differ 2006;13:179 ^ 88. dimensional structure database. JMed Chem 2004;6: 47. Glover CJ, Hite K, DeLosh R, et al. A high-through- 52. Reed JC, Pellecchia M. Apoptosis-based therapies 2430^40. put screen for identification of molecular mimics of for hematologic malignancies. Blood 2005;106: 58. Davydov IV, Woods D, Safiran YJ, et al. Assay Smac/DIABLO utilizing a fluorescence polarization 408^18. for ubiquitin ligase activity: high-throughput screen assay Barrett esophagus. Anal Biochem 2003;320: 53. Wright CW, Duckett CS. Reawakening the cellular for inhibitors of HDM2. J Biomol Screen 2004;9: 157 ^ 6 9. death program in neoplasia through the therapeutic 695 ^ 703.

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Herman H. Cheung, Eric C. LaCasse and Robert G. Korneluk

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