Rational design, synthesis and characterization of potent, drug-like monomeric Smac mimetics as pro-apoptotic anticancer agents

Bianchi, Aldo; Ugazzi, Marcello; Ferrante, Luca; Lecis, Daniele; Scavullo, Cinzia; Mastrangelo, Eloise; Seneci, Pierfausto

doi:10.1016/j.bmcl.2012.01.098

Cited by 8 publications

(8 citation statements)

References 44 publications

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“…The synthesis of Smac127 was carried out as described elsewhere [ 19 , 20 ]. Smac127 was dissolved and diluted in distilled sterile water for in vitro administration.…”

Section: Methodsmentioning

confidence: 99%

Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes

Lattuada

Gualtierotti

Crotta

et al. 2016

Mediators of Inflammation

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Rheumatoid arthritis (RA) is characterized by synovial inflammation and hyperplasia. Fibroblast-like synoviocytes (FLSs) are apoptosis-resistant and contribute to the pathogenesis of RA by producing cytokines and proteolytic enzymes, which degrade the extracellular matrix. We evaluated the proapoptotic and anti-inflammatory activity of the small molecule Smac127 on RA-FLSs cultured in synovial fluid (SF), in order to reproduce the physiopathological environmental characteristic of RA joints. In this context, Smac127 induces apoptosis by inhibiting apoptosis proteins (IAPs). This inhibition activates caspase 3 and restores the apoptotic pathway. In addition, Smac127 induces a significant inhibition of the secretion of IL-15 and IL-6, stimulation of pannus formation, and damage of bone and cartilage in RA. Also the secretion of the anti-inflammatory cytokine IL-10 is dramatically increased in the presence of Smac127. The cartilage destruction in RA patients is partly mediated by metalloproteinases; here we show that the MMP-1 production by fibroblasts cultured in SF is significantly antagonized by Smac127. Conversely, this molecule has no significant effects on RANKL and OPG production. Our observations demonstrate that Smac127 has beneficial regulatory effects on inflammatory state of RA-FLSs and suggest a potential use of Smac127 for the control of inflammation and disease progression in RA.

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“…The synthesis of Smac127 was carried out as described elsewhere [ 19 , 20 ]. Smac127 was dissolved and diluted in distilled sterile water for in vitro administration.…”

Section: Methodsmentioning

confidence: 99%

Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes

Lattuada

Gualtierotti

Crotta

et al. 2016

Mediators of Inflammation

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“…1), endowed with good cell-free potency against IAPs and moderate cytotoxicity. 28,29 Since α V integrins are overexpressed on the surface of cancer cells, their ligands can be used as tumour-homing/antiangiogenic peptidomimetics for site-directed delivery of cytotoxic drugs. 30 For example, the cyclic RGD ligand-doxorubicin conjugate 8 31 (Fig.…”

Section: Project Rationalementioning

confidence: 99%

Synthesis and biological evaluation of dual actioncyclo-RGD/SMAC mimetic conjugates targeting α_vβ₃/α_vβ₅integrins and IAP proteins

et al. 2014

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The rational design, synthesis and in vitro biological evaluation of dual action conjugates 11-13, containing a tumour targeting, integrin αvβ3/αvβ5 ligand portion and a pro-apoptotic SMAC mimetic portion (cyclo-RGD/SMAC mimetic conjugates) are reported. The binding strength of the two separate units is generally maintained by these dual action conjugates. In particular, the connection between the separate units (anchor points on each unit; nature, length and stability of the linker) influences the activity of each portion against its molecular targets (integrins αvβ3/αvβ5 for cyclo-RGD, IAP proteins for SMAC mimetics). Each conjugate portion tolerates different substitutions while preserving the binding affinity for each target.

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“…Several Smac-mimetic compounds have been synthesised in drug development. Previous studies used computational, NMR, and X-ray data to establish a preliminary structure–activity relationship for XIAP inhibitors, and this led to the design of optimised analogues [ 15 , 16 ]. Smac mimetics can target different members of the IAP family and cause proteasomal-dependent degradation of cIAP1 and cIAP2 [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

“…1 ) in the current study. The synthesis of Smac was carried out as described elsewhere [ 15 , 16 ]. Smac molecules were dissolved and diluted in water.…”

Section: Methodsmentioning

confidence: 99%

Proapoptotic Activity of a Monomeric Smac Mimetic on Human Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis

Lattuada¹,

Casnici²,

Crotta³

et al. 2014

Inflammation

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Inhibitors of apoptosis proteins (IAPs) block cell death in response to diverse stimuli. The mitochondrial protein, second mitochondria-derived activator of caspase (Smac), negatively regulates IAP inhibition of caspase activity. We investigated the proapoptotic activity of a synthetic Smac (Smac 066) on fibroblast-like synoviocytes (FLS) derived from patients with active rheumatoid arthritis (RA). We found that Smac 066 induced significant apoptosis in all RA-FLS samples. Furthermore, IAPs, which are upregulated in RA-FLS, were downregulated by Smac 066. This suggested that IAPs upregulation was responsible for RA-FLS sensitivity to Smac 066. Next, we analysed caspase activation and found that Smac 066 was associated with caspase 8 and caspase 3 activities. We then investigated the mechanism underlying Smac 066 downregulation of IAPs in RA-FLS with an apoptotic pathway array. Interestingly, Smac 066 significantly upregulated IGFBP-5, a protein involved in differentiation, apoptosis, and osteoblastic activation. Smac 066 may represent a new therapeutic approach to RA treatment.

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Rational design, synthesis and characterization of potent, drug-like monomeric Smac mimetics as pro-apoptotic anticancer agents

Cited by 8 publications

References 44 publications

Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes

Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes

Synthesis and biological evaluation of dual actioncyclo-RGD/SMAC mimetic conjugates targeting α_vβ₃/α_vβ₅integrins and IAP proteins

Proapoptotic Activity of a Monomeric Smac Mimetic on Human Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis

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Rational design, synthesis and characterization of potent, drug-like monomeric Smac mimetics as pro-apoptotic anticancer agents

Cited by 8 publications

References 44 publications

Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes

Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes

Synthesis and biological evaluation of dual actioncyclo-RGD/SMAC mimetic conjugates targeting αvβ3/αvβ5integrins and IAP proteins

Proapoptotic Activity of a Monomeric Smac Mimetic on Human Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis

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Synthesis and biological evaluation of dual actioncyclo-RGD/SMAC mimetic conjugates targeting α_vβ₃/α_vβ₅integrins and IAP proteins