A high-throughput screen for identification of molecular mimics of Smac/DIABLO utilizing a fluorescence polarization assay

Glover, Constance J.; Hite, Karen M.; DeLosh, Renee; Scudiero, Dominic A.; Fivash, Matthew J.; Smith, Lindsey; Fisher, Robert J.; Wu, Jing; Shi, Yigong; Kipp, Rachael A.; McLendon, George; Sausville, Edward A.; Shoemaker, Robert H.

doi:10.1016/s0003-2697(03)00389-0

Cited by 32 publications

(21 citation statements)

References 40 publications

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“…In contrast, smallmolecule and peptidyl SMAC-mimics sensitize cells to chemotherapy, but are generally inactive as single agents. [41][42][43][44] Differences in induction of cell death by polyphenylurea XIAP antagonists versus the SMAC-mimics may relate to their different effects on caspases. Peptidyl and chemical SMAC-mimics derepress caspase 9 by binding the BIR3 domain of XIAP, but caspases 3 and 7 remain blocked as SMAC-mimics do not efficiently inhibit the BIR2 domain of XIAP.…”

Section: Discussionmentioning

confidence: 99%

Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells

Carter

Gronda

Wang

et al. 2005

Blood

117

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IntroductionAt a fundamental level, patients with acute leukemia do not respond to treatment because the malignant blasts are not eradicated by current chemotherapy. In part, this failure is due to defects in apoptosis pathways. 1 Therefore, agents that overcome roadblocks to apoptosis could be therapeutically useful for this disease.Classically, apoptosis is caused by the activation of caspases, a family of intracellular cysteine proteases that cleave substrates at aspartic acid residues. 2,3 Currently, at least 4 pathways for initiation of caspase activation exist: (1) the mitochondrial pathway with cytochrome c; (2) the death receptor pathway with the tumor necrosis factor (TNF) family of death receptors; (3) direct caspase activation by cytolytic T-cell protease Granzyme B; and (4) a pathway connected to the endoplasmic reticulum. These pathways launch a proteolytic cascade, in which upstream (initiator) caspases cleave and activate downstream (effector) caspases.The inhibitor of apoptosis proteins (IAPs) are a family of endogenous caspase inhibitors that share a common baculoviral IAP repeat (BIR) domain. To date, 8 IAP family members exist in humans. Of these, XIAP is probably the best characterized with respect to its structure and biochemical mechanisms. XIAP inhibits caspases 3, 7, and 9, but not caspases 1, 6, 8, or 10. 4 XIAP contains 3 tandem baculovirus IAP repeat (BIR) domains and a really interesting new gene (RING) domain. The second BIR domain of XIAP (BIR2) inhibits caspases 3 and 7, while the third BIR domain (BIR3) inhibits caspase 9. Through their ability to inhibit caspases, IAPs act as antiapoptotic proteins [5][6][7][8][9][10] and are promising therapeutic targets. Inhibition of XIAP by antisense strategies or peptides that bind and inhibit the BIR3 domain of XIAP sensitizes malignant cells to chemotherapy. [11][12][13][14][15][16][17][18] Based on the knowledge that XIAP directly inhibits active caspase 3, we devised an enzymatic derepression assay to screen for molecules that relieve protease inhibition. Using this assay, we screened combinatorial libraries of chemical compounds and identified active agents based on different pharmacophores. The initial report of these XIAP inhibitors described a series of compounds based on the polyphenylurea pharmacophore including the active compound N- -methyl-NЈ-phenylurea (1396-12) and structural analogues. 19 Corresponding to their activity in the enzymatic assay, active polyphenylurea-based inhibitors but not inactive controls, induced rapid apoptosis of several types of tumor cell lines. 19 We determined that active compounds inhibit XIAP by binding its BIR2 domain at a site distinct from the binding pocket of the endogenous XIAP inhibitor second modulator of apoptotic proteases (SMAC). 20 Given the potential therapeutic utility of IAP inhibition, we tested these chemical IAP inhibitors in cultured leukemia cell lines For personal use only. on June 19, 2019. by guest www.bloodjournal.org From and primary acute myelogenous leukemia (AML) patie...

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Section: Discussionmentioning

confidence: 99%

Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells

Carter

Gronda

Wang

et al. 2005

Blood

117

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“…There are 3 main screening strategies to search for IAP antagonists. First, peptides that structurally resemble the N terminus of Smac were shown to bind to the BIR3 pocket of XIAP, subsequently leading to inhibition of XIAP (86). The development of these peptides is promising; however, further work is required to determine whether these peptides can induce apoptosis or sensitize cells to chemotherapy.…”

Section: Caspases As Targets In Drug Developmentmentioning

confidence: 99%

Caspases: pharmacological manipulation of cell death

Lavrik

Golks

Krammer

2005

Journal of Clinical Investigation

558

411

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Caspases, a family of cysteine proteases, play a central role in apoptosis. During the last decade, major progress has been made to further understand caspase structure and function, providing a unique basis for drug design. This Review gives an overview of caspases and their classification, structure, and substrate specificity. We also describe the current knowledge of how interference with caspase signaling can be used to pharmacologically manipulate cell death.

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“…The first strategy was based on the ability of SMAC peptides to bind to the BIR3 pocket of XIAP. Using fluorescence polarization assays or similar fluorescence-based assays, peptides and small molecules were identified that compete with SMAC peptides for binding to the BIR3 pocket (94,95). Further work, however, is required to determine whether these peptides can induce apoptosis or sensitize cells to chemotherapy.…”

Section: Inhibitor Of Apoptosis Proteins As Therapeutic Targetsmentioning

confidence: 99%

Inhibitor of Apoptosis Proteins: Translating Basic Knowledge into Clinical Practice

2004

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The inhibitor of apoptosis proteins (IAPs) are a family of antiapoptotic proteins that bind and inhibit caspases 3, 7, and/or 9, but not caspase 8. Growing evidence also indicates that IAPs also modulate cell division, cell cycle progression, and signal transduction pathways. As our basic understanding of IAPs has increased, the knowledge is being translated into clinically useful applications in the diagnosis and treatment of malignancy. For example, IAPs such as survivin are being investigated as diagnostic markers for the presence of occult malignancy. In addition, IAP overexpression is a poor prognostic marker in a variety of solid tumors and hematologic malignancies. Finally, IAPs are attractive therapeutic targets, and efforts are under way to develop antisense and chemical IAP inhibitors that may be useful for the treatment of a variety of malignancies. For all of these potential clinical applications, however, the challenge remains to incorporate these findings into actual clinical practice.

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A high-throughput screen for identification of molecular mimics of Smac/DIABLO utilizing a fluorescence polarization assay

Cited by 32 publications

References 40 publications

Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells

Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells

Caspases: pharmacological manipulation of cell death

Inhibitor of Apoptosis Proteins: Translating Basic Knowledge into Clinical Practice

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