Rationally Designed Less Toxic SPD‐304 Analogs and Preliminary Evaluation of Their TNF Inhibitory Effects

Alexiou, Panagiotis; Papakyriakou, Athanasios; Ntougkos, Evangelos; Papaneophytou, Christos; Liepouri, Fotini; Mettou, Anthi; Katsoulis, Ioannis A.; Maranti, Anna; Tsiliouka, Katerina; Strongilos, A. T.; Chaitidou, Sotiria; Douni, Eleni; Kontopidis, George; Kollias, George; Couladouros, Elias A.; Eliopoulos, Elias

doi:10.1002/ardp.201400198

Cited by 26 publications

(38 citation statements)

References 39 publications

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“…The compound SPD- 304 targets TNF directly and has been shown to inhibit activity by destabilising the TNF trimer, resulting in a dimer that is no longer able to interact with receptor 4 . Although this strategy has so far not led to molecules capable of being developed, work is continuing in this area 5–7 . The TNF trimer may also be induced to disassemble by aggregating small molecules 8 .…”

Section: Introductionmentioning

confidence: 99%

Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

et al. 2019

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Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions.

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Section: Introductionmentioning

confidence: 99%

Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

et al. 2019

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“…Mouhsine et al used combined in silico/in vitro/in vivo screening approaches to identify orally available TNF-α inhibitors with IC 50 of 10 μM (Figure 1 , Benzenesulfonamide-1 ; Mouhsine et al, 2017 ). Other efforts to develop TNF-α inhibitors were also reported (Mancini et al, 1999 ; Buller et al, 2009 ; Leung et al, 2011 ; Hu et al, 2012 ; Alexiou et al, 2014 ; Ma et al, 2014 ; Kang et al, 2016 ). However, due to the low potency and high cytotoxicity, small molecule TNF-α inhibitors still have a long way to go for clinical applications (Davis and Colangelo, 2013 ).…”

Section: Introductionmentioning

confidence: 94%

Design, Synthesis, and Evaluation of Dihydrobenzo[cd]indole-6-sulfonamide as TNF-α Inhibitors

et al. 2018

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Tumor necrosis factor-α (TNF-α) plays a pivotal role in inflammatory response. Dysregulation of TNF can lead to a variety of disastrous pathological effects, including auto-inflammatory diseases. Antibodies that directly targeting TNF-α have been proven effective in suppressing symptoms of these disorders. Compared to protein drugs, small molecule drugs are normally orally available and less expensive. Till now, peptide and small molecule TNF-α inhibitors are still in the early stage of development, and much more efforts should be made. In a previously study, we reported a TNF-α inhibitor, EJMC-1 with modest activity. Here, we optimized this compound by shape screen and rational design. In the first round, we screened commercial compound library for EJMC-1 analogs based on shape similarity. Out of the 68 compounds tested, 20 compounds showed better binding affinity than EJMC-1 in the SPR competitive binding assay. These 20 compounds were tested in cell assay and the most potent compound was 2-oxo-N-phenyl-1,2-dihydrobenzo[cd]indole-6-sulfonamide (S10) with an IC50 of 14 μM, which was 2.2-fold stronger than EJMC-1. Based on the docking analysis of S10 and EJMC-1 binding with TNF-α, in the second round, we designed S10 analogs, purchased seven of them, and synthesized seven new compounds. The best compound, 4e showed an IC50-value of 3 μM in cell assay, which was 14-fold stronger than EJMC-1. 4e was among the most potent TNF-α organic compound inhibitors reported so far. Our study demonstrated that 2-oxo-N-phenyl-1,2-dihydrobenzo[cd]indole-6-sulfonamide analogs could be developed as potent TNF-α inhibitors. 4e can be further optimized for its activity and properties. Our study provides insights into designing small molecule inhibitors directly targeting TNF-α and for protein–protein interaction inhibitor design.

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“…Previously, we designed, synthesized, and biologically evaluated 38 SPD304 analogues. 10,11 Herein, we have designed and synthesized 16 new compounds ( 5f , 12 , 13 , 14a–d , 15a – c , 16a – e , 17 ) and studied the combined total of 55 compounds (i.e., SPD304 and 54 analogues; Fig. 1 ).…”

Section: Introductionmentioning

confidence: 99%

“…The design of these 54 analogues focused on eliminating SPD304 toxicity and strengthening the interactions between the inhibitor and the binding site of TNF-α. 10,11…”

Section: Introductionmentioning

confidence: 99%

Aqueous Solubility Enhancement for Bioassays of Insoluble Inhibitors and QSPR Analysis: A TNF-α Study

et al. 2018

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The aim of this study is to improve the aqueous solubility of a group of compounds without interfering with their bioassay as well as to create a relevant prediction model. A series of 55 potential small-molecule inhibitors of tumor necrosis factor-alpha (TNF-α; SPD304 and 54 analogues), many of which cannot be bioassayed because of their poor solubility, was used for this purpose. The solubility of many of the compounds was sufficiently improved to allow measurement of their respective dissociation constants (K). Parameters such as dissolution time, initial state of the solute (solid/liquid), co-solvent addition (DMSO and PEG3350), and sample filtration were evaluated. Except for filtration, the remaining parameters affected aqueous solubility, and a solubilization protocol was established according to these. The aqueous solubility of the 55 compounds in 5% DMSO was measured with this protocol, and a predictive quantitative structure property relationship model was developed and fully validated based on these data. This classification model separates the insoluble from the soluble compounds and predicts the solubility of potential small-molecule inhibitors of TNF-α in aqueous solution (containing 5% DMSO as co-solvent) with an accuracy of 81.2%. The domain of applicability of the model indicates the type of compounds for which estimation of aqueous solubility can be confidently predicted.

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Rationally Designed Less Toxic SPD‐304 Analogs and Preliminary Evaluation of Their TNF Inhibitory Effects

Cited by 26 publications

References 39 publications

Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

Design, Synthesis, and Evaluation of Dihydrobenzo[cd]indole-6-sulfonamide as TNF-α Inhibitors

Aqueous Solubility Enhancement for Bioassays of Insoluble Inhibitors and QSPR Analysis: A TNF-α Study

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