Homo- and heterodimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part I: Synthesis

Manzoni, Leonardo; Belvisi, Laura; Bianchi, Aldo; Conti, Annalisa; Drago, Carmelo; Matteo, Marilenia De; Ferrante, Luca; Mastrangelo, Eloise; Perego, Paola; Potenza, Donatella; Scolastico, Carlo; Servida, Federica; Timpano, Gabriele; Rizzo, Vincenzo; Seneci, Pierfausto

doi:10.1016/j.bmc.2012.09.020

Cited by 20 publications

(27 citation statements)

References 56 publications

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“…Peptides that mimic the aminoterminal IAP-binding sequence of Smac, so-called Smac mimetics, were found to enhance the cytotoxicity of chemotherapeutic agents and death ligands such as TRAIL [30], [31]. Indeed, co-treatment of Caco-2tet K-Ras G12V cells with Db αEGFR -scTRAIL and a previously developed highly efficient dimeric Smac mimetic, SM83 [19], [20], decreased cell viability by 35% compared with the single treatments. This was efficiently blocked by Z-VAD, proving the involvement of caspase activation in the case of the combinatorial treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

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EGFR-Targeted TRAIL and a Smac Mimetic Synergize to Overcome Apoptosis Resistance in KRAS Mutant Colorectal Cancer Cells

et al. 2014

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TRAIL is a death receptor ligand that induces cell death preferentially in tumor cells. Recombinant soluble TRAIL, however, performs poorly as an anti-cancer therapeutic because oligomerization is required for potent biological activity. We previously generated a diabody format of tumor-targeted TRAIL termed DbαEGFR-scTRAIL, comprising single-stranded TRAIL molecules (scTRAIL) and the variable domains of a humanized variant of the EGFR blocking antibody Cetuximab. Here we define the bioactivity of DbαEGFR-scTRAIL with regard to both EGFR inhibition and TRAIL receptor activation in 3D cultures of Caco-2 colorectal cancer cells, which express wild-type K-Ras. Compared with conventional 2D cultures, Caco-2 cells displayed strongly enhanced sensitivity toward DbαEGFR-scTRAIL in these 3D cultures. We show that the antibody moiety of DbαEGFR-scTRAIL not only efficiently competed with ligand-induced EGFR function, but also determined the apoptotic response by specifically directing DbαEGFR-scTRAIL to EGFR-positive cells. To address how aberrantly activated K-Ras, which leads to Cetuximab resistance, affects DbαEGFR-scTRAIL sensitivity, we generated stable Caco-2tet cells inducibly expressing oncogenic K-RasG12V. In the presence of doxycycline, these cells showed increased resistance to DbαEGFR-scTRAIL, associated with the elevated expression of the anti-apoptotic proteins cIAP2, Bcl-xL and FlipS. Co-treatment of cells with the Smac mimetic SM83 restored the DbαEGFR-scTRAIL-induced apoptotic response. Importantly, this synergy between DbαEGFR-scTRAIL and SM83 also translated to 3D cultures of oncogenic K-Ras expressing HCT-116 and LoVo colorectal cancer cells. Our findings thus support the notion that DbαEGFR-scTRAIL therapy in combination with apoptosis-sensitizing agents may be promising for the treatment of EGFR-positive colorectal cancers, independently of their KRAS status.

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Section: Resultsmentioning

confidence: 99%

“…Db αEGFR -scTRAIL was produced in HEK293 cells and purified from cell culture supernatants [15]. The synthesis and purification of SM83 was described previously [19], [20].…”

Section: Methodsmentioning

confidence: 99%

EGFR-Targeted TRAIL and a Smac Mimetic Synergize to Overcome Apoptosis Resistance in KRAS Mutant Colorectal Cancer Cells

et al. 2014

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“…28, 29 One of these molecules, SM83, inhibited the growth of SM-sensitive human mammary adenocarcinoma MDA-MB231 and rhabdomyosarcoma Kym-1, but not of other cell lines. Here, we use two murine xenograft models of cancer ascites to show that SM83, when administered in monotherapy, increases the survival of these mice by targeting tumour-associated macrophages.…”

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confidence: 99%

Smac mimetics induce inflammation and necrotic tumour cell death by modulating macrophage activity

Lecis¹,

Cesare²,

Perego³

et al. 2013

Cell Death Dis

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Smac mimetics (SMs) comprise a class of small molecules that target members of the inhibitor of apoptosis family of pro-survival proteins, whose expression in cancer cells hinders the action of conventional chemotherapeutics. Herein, we describe the activity of SM83, a newly synthesised dimeric SM, in two cancer ascites models: athymic nude mice injected intraperitoneally with IGROV-1 human ovarian carcinoma cells and immunocompetent BALB/c mice injected with murine Meth A sarcoma cells. SM83 rapidly killed ascitic IGROV-1 and Meth A cells in vivo (prolonging mouse survival), but was ineffective against the same cells in vitro. IGROV-1 cells in nude mice were killed within the ascites by a non-apoptotic, tumour necrosis factor (TNF)-dependent mechanism. SM83 administration triggered a rapid inflammatory event characterised by host secretion of TNF, interleukin-1β and interferon-γ. This inflammatory response was associated with the reversion of the phenotype of tumour-associated macrophages from a pro-tumoural M2- to a pro-inflammatory M1-like state. SM83 treatment was also associated with a massive recruitment of neutrophils that, however, was not essential for the antitumoural activity of this compound. In BALB/c mice bearing Meth A ascites, SM83 treatment was in some cases curative, and these mice became resistant to a second injection of cancer cells, suggesting that they had developed an adaptive immune response. Altogether, these results indicate that, in vivo, SM83 modulates the immune system within the tumour microenvironment and, through its pro-inflammatory action, leads cancer cells to die by necrosis with the release of high-mobility group box-1. In conclusion, our work provides evidence that SMs could be more therapeutically active than expected by stimulating the immune system.

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“…42 However the use of RANEY® nickel and milder reactions conditions provided clean access to a variety of benzylamines from aromatic nitriles. 43 Similarly, the reduction of olefin and nitrile moieties of 19 required the use of RANEY® Ni catalyst, 70 bar and 70°C (Scheme 4). 43 Similarly, the reduction of olefin and nitrile moieties of 19 required the use of RANEY® Ni catalyst, 70 bar and 70°C (Scheme 4).…”

Section: Nitrile Reductionsmentioning

confidence: 99%

“…In relation to amide reduction, flow chemistry offers an approach to avoiding the traditionally hazardous and poor atom economy associated with transfer hydrogenation. 43,47,48 The relatively mild reducing conditions of azide moieties have been exploited for the chemoselective reduction of 27, eliminating over reduction of the ketone moiety (Scheme 7). 46 In contrast azide reduction occurs under significantly milder conditions (cf.…”

Section: Nitrile Reductionsmentioning

confidence: 99%

The expanding utility of continuous flow hydrogenation

et al. 2015

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There has been an increasing body of evidence that flow hydrogenation enhances reduction outcomes across a wide range of synthetic transformations. Moreover flow reactors enhance laboratory safety with pyrophoric catalysts contained in sealed cartridges and hydrogen generated in situ from water. This mini-review focuses on recent applications of flow chemistry to mediate nitro, imine, nitrile, amide, azide, and azo reductions. Methodologies to effect de-aromatisation, hydrodehalogenation, in addition to olefin, alkyne, carbonyl, and benzyl reductions are also examined. Further, protocols to effect chemoselective reductions and enantioselective reductions are highlighted. Together these applications demonstrate the numerous advantages of performing hydrogenation under flow conditions which include enhanced reaction throughput, yields, simplified workup, and the potential applicability to multistep and cascade synthetic protocols.

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Homo- and heterodimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part I: Synthesis

Cited by 20 publications

References 56 publications

EGFR-Targeted TRAIL and a Smac Mimetic Synergize to Overcome Apoptosis Resistance in KRAS Mutant Colorectal Cancer Cells

EGFR-Targeted TRAIL and a Smac Mimetic Synergize to Overcome Apoptosis Resistance in KRAS Mutant Colorectal Cancer Cells

Smac mimetics induce inflammation and necrotic tumour cell death by modulating macrophage activity

The expanding utility of continuous flow hydrogenation

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