Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain

Liu, Zhihong; Sun, Chaohong; Olejniczak, Edward T.; Meadows, Robert P.; Betz, Stephen F.; Oost, Thorsten; Herrmann, Julia; Wu, Joe C.; Fesik, Stephen W.

doi:10.1038/35050006

Cited by 593 publications

(590 citation statements)

References 25 publications

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“…1 H chemical shifts are reported with CDCl 3 (7.27 ppm) or HDO (4.70 ppm) as internal standards. 13 2 g). The mixture was stirred under H 2 for 8 h then filtered through celite and the filtrate was evaporated to give an ester.…”

Section: Methodsmentioning

confidence: 97%

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Design, Synthesis, and Characterization of a Potent, Nonpeptide, Cell-Permeable, Bivalent Smac Mimetic That Concurrently Targets Both the BIR2 and BIR3 Domains in XIAP

et al. 2007

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XIAP is a central apoptosis regulator that inhibits apoptosis by binding to and inhibiting the effectors caspase-3/-7 and an initiator caspase-9 through its BIR2 and BIR3 domains, respectively. Smac protein in its dimeric form effectively antagonizes XIAP by concurrently targeting both its BIR2 and BIR3 domains. We report the design, synthesis and characterization of a non-peptide, cell-permeable, bivalent small-molecule (SM-164) which mimics Smac protein for targeting XIAP. Our study shows that SM-164 binds to XIAP containing both BIR domains with an IC 50 value of 1.39 nM, being 300 and 7000-times more potent than its monovalent counterparts and the natural Smac AVPI peptide, respectively. SM-164 concurrently interacts with both BIR domains in XIAP and functions as an ultra-potent antagonist of XIAP in both cell-free functional and cell-based assays. SM-164 targets cellular XIAP and effectively induces apoptosis at concentrations as low as 1 nM in leukemia cancer cells, while having a minimal toxicity to normal human primary cells at 10,000 nM. The potency of bivalent SM-164 in binding, functional and cellular assays is 2-3 orders of magnitude higher than its corresponding monovalent Smac mimetics.

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Section: Methodsmentioning

confidence: 97%

“…The mixture was stirred at room temperature overnight then condensed and the residue was purified by chromatography to give the amide 16 (379 mg, 67% over four steps). 1 45 (m, 15H); 13 …”

Section: (3s6s10as)-6-((s)-2-acetamido-3-(1h-indol-3-yl)propanamidomentioning

confidence: 99%

Design, Synthesis, and Characterization of a Potent, Nonpeptide, Cell-Permeable, Bivalent Smac Mimetic That Concurrently Targets Both the BIR2 and BIR3 Domains in XIAP

et al. 2007

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“…9 Smac binds to IAP proteins as an endogenous neutralizer. 10 High expression levels of IAP proteins in CLL may contribute to cell death resistance. IAP proteins, in particular XIAP, are overexpressed in CLL and this overexpression confers chemoresistance and is associated with a progressive course.…”

mentioning

confidence: 99%

Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia

Opel

Schnaiter

Dodier

et al. 2015

Intl Journal of Cancer

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Inhibitor of apoptosis (IAP) proteins are highly expressed in chronic lymphocytic leukemia (CLL) cells and contribute to evasion of cell death and poor therapeutic response. Here, we report that Smac mimetic BV6 dose-dependently induces cell death in 28 of 51 (54%) investigated CLL samples, while B-cells from healthy donors are largely unaffected. Importantly, BV6 is significantly more effective in prognostic unfavorable cases with, e.g., non-mutated VH status and TP53 mutation than samples with unknown or favorable prognosis. The majority of cases with 17p deletion (10/12) and Fludarabine refractory cases respond to BV6, indicating that BV6 acts independently of p53. BV6 also triggers cell death under survival conditions mimicking the microenvironment, e.g., by adding CD40 ligand or conditioned medium. Gene expression profiling identifies cell death, NF-jB and redox signaling among the top pathways regulated by BV6 not only in CLL but also in core-binding factor (CBF) acute myeloid leukemia (AML). Consistently, BV6 stimulates production of reactive oxygen species (ROS), which are contributing to BV6-induced cell death, since antioxidants reduce cell death. While BV6 causes degradation of cellular inhibitor of apoptosis (cIAP)1 and cIAP2 and nuclear factor-kappaB (NF-jB) pathway activation in primary CLL samples, BV6 induces cell death independently of caspase activity, receptor-interacting protein (RIP)1 activity or tumor necrosis factor (TNF)a, as zVAD.fmk, necrostatin-1 or TNFa-blocking antibody Enbrel fail to inhibit cell death. Together, these novel insights into BV6-regulated cell death in CLL have important implications for developing new therapeutic strategies to overcome cell death resistance especially in poor prognostic CLL subgroups.Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the Western world. 1 Key prognostic factors besides the Rai and Binet stage are chromosomal aberrations like 17p or 11q deletion, TP53 mutation and immunoglobulin heavy-chain variable region gene (IGVH) mutation status. Although individualized therapeutic strategies have been developed, the disease is still incurable. Especially patients with 17p deletion and TP53 mutation have a very poor prognosis. 2 Therefore, new therapeutic targets that act independently of functional p53 in CLL are needed.CLL is characterized by the accumulation of Blymphocytes which has been largely attributed to defective cell death pathways rather than to aberrant proliferation. [3][4][5] Apoptosis represents one of the key forms of programmed cell death. 6 Necroptosis is a caspase-independent mode of programmed cell death that typically occurs when essential factors of apoptosis such as caspases are inhibited and is regulated by RIP1 and RIP3. 7 Inhibitor of apoptosis (IAP) proteins are major regulators of cell death and survival processes. X-linked inhibitor of apoptosis (XIAP) acts as direct caspase inhibitor, 8 while cIAP1 and -2 were shown to protect cells from cell death by acting primarily as E3 ubiquitin liga...

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“…Cependant, l'enthousiasme initial suscité par cette dernière approche doit être tempéré [22] : en effet, les algorithmes actuels ne prennent, pour l'instant, pas ou peu en compte des phénomènes primordiaux tels que la flexibilité conformationnelle des protéines ou l'influence du solvant et des ions dans l'interaction protéine-ligand. [35]). D. Un tripeptide non naturel optimisé inhibe l'interaction avec une IC 50 de 5 nM (pdb 1TFT, [39]).…”

Section: Conception De Novounclassified