Recognition of Smac‐mimetic compounds by the BIR domain of cIAP1

Abstract

Inhibitor of apoptosis proteins (IAPs) are negative regulators of apoptosis. As IAPs are overexpressed in many tumors, where they confer chemoresistance, small molecules inactivating IAPs have been proposed as anticancer agents. Accordingly, a number of IAP-binding proapoptotic compounds that mimic the sequence corresponding to the N-terminal tetrapeptide of Smac/DIABLO, the natural endogenous IAPs inhibitor, have been developed. Here, we report the crystal structures of the BIR3 domain of cIAP1 in complex with Smac037, a Smac-mimetic known to bind potently to the XIAP-BIR3 domain and to induce degradation of cIAP1, and in complex with the novel Smac-mimetic compound Smac066. Thermal stability and fluorescence polarization assays show the stabilizing effect and the high affinity of both Smac037 and Smac066 for cIAP1-and cIAP2-BIR3 domains.

Piperine derivatives as potential inhibitors of Survivin: An in silico molecular docking

“…It has been reported that Survivin as a member of IAPs can directly bind to caspases through the BIR domain and inhibit their activities [4]. On the other hand, when the intrinsic apoptosis pathway is triggered, the IAP regulatory protein Smac which is normally restricted to the inter-membrane space of mitochondria is released to the cytosol and binds to a cavity on BIR domain.…”

“…The identification of Smac as a natural inhibitor of IAPs has motivated scientists to explore Smac mimetics. It has been reported that compounds synthesized based on Smac structure can bind to BIR domains of IAPs, causing caspases to be released from this unit, and thus promoting apoptosis [4]. Survivin, the smallest member of IAPs family is a 16.5 kDa protein with 142 amino acid residues.…”

“…It has been shown that binding of Survivin to the phosphorylated form of the histone H3 N-terminus (H3-T3ph) is essential in CPC formation and thereby functions as a key regulator of chromosomal segregation and cytokinesis [7]. It was shown that Survivin inhibits apoptosis both in vitro and in vivo [8], perhaps via interactions with different regulators of two apoptosis pathways [4]. Survivin is expressed in fetal tissues and different types of cancer cells [9].…”

Expression of executioner procaspases and their activation by a procaspase-activating compound in chronic lymphocytic leukemia cells

“…These data imply that B-PAC-1-mediated caspase activation is encountered by the high levels of IAPs, and therefore suppressing the functional IAPs with addition of smac mimetic may enhance apoptosis in CLL lymphocytes. Smac066 is a monomeric smac mimetic 26 with anticancer effect on MDA-MB231, HL-60, PC-3, and CLL cells. 27,28 B-PAC-1 and Smac066 in combination increased apoptosis in CLL lymphocytes more than either agent alone ( Figure 7C).…”

Withanone as an inhibitor of survivin: A potential drug candidate for cancer therapy

“…It has been shown that synthetic compounds based on Smac can bind to the BIR domains of IAPs, relieving caspase binding, thus promoting apoptosis. (Cossu et al, , 2010Li et al, 2004;Seneci et al, 2009;Zobel et al, 2006;Gyrd-Hansen & Meier, 2010). In addition, results have shown that Smac-mimetic compounds can kill cancer cells by inducing the "ubiquitin-dependent" degradation of cIAP1 and cIAP2.…”