Discovery of 5-(2′,4′-difluorophenyl)-salicylanilides as new inhibitors of receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis

Lee, Chia Chung; Liu, Fei Lan; Chen, Chun-Liang; Chen, Tsung Chih; Chang, Deh Ming; Huang, Hsu Shan

doi:10.1016/j.ejmech.2015.05.015

Cited by 30 publications

(32 citation statements)

References 48 publications

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“…According to the relationship between symptom distress and TRACP5a (Table 4), we further expected that a potential inhibitor of TRACP5a could efficiently contribute to relieve the fatigue, overcome the sleep disturbance, alleviate the pain, treat the depression, and clear the confusion. Because TRACP5a, which generally belongs to the TRACP family, also expresses in osteoclasts as an osteoclast biomarker gene, 29 several researchers have recently demonstrated that TRACP can be reduced by some drugs, such as GF109203X, 52 receptor activator of the nuclear factor .B ligand (RANKL) inhibitors, 53 and tacrolimus, 54 to attenuate osteoclastogenesis. In addition, RANKL induced monocyte/macrophage cells for osteoclastic differentiation 55 and generation of TRACP-positive multinucleated cells in bone marrowYderived monocytes.…”

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confidence: 99%

The Relationship Between Inflammatory Biomarkers and Symptom Distress in Lung Cancer Patients Undergoing Chemotherapy

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Section: Discussionmentioning

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The Relationship Between Inflammatory Biomarkers and Symptom Distress in Lung Cancer Patients Undergoing Chemotherapy

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“…Accordingly, our previously study have demonstrated NDMC101, a salicylanidide derivative, inhibited RANKL-induced osteoclast differentiation by suppressing NFATc1 and NF-KB activity, and ameliorates paw swelling in collagen-induced arthritis mice 24 . In addition, a new salicylanilide derivatives 6d and 6i, that was synthesized from the lead compound NDMC101, could also suppressed RANKL-stimulated osteoclastogenesis 25 . On the basis of these findings, salicylanilide-derived small molecules could have potential as anti-osteoclastogenesis drugs.…”

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confidence: 99%

The Simultaneous Inhibitory Effect of Niclosamide on RANKL-Induced Osteoclast Formation and Osteoblast Differentiation

et al. 2017

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The bone destruction disease including osteoporosis and rheumatoid arthritis are caused by the imbalance between osteoblastogenesis and osteoclastogenesis. Inhibition of the NF-κB pathway was responsible for decreased osteoclastogenesis. Recently many studies indicated that niclosamide, the FDA approved an antihelminth drug, inhibits prostate and breast cancer cells growth by targeting NF-κB signaling pathways. This study evaluated the effects of niclosamide on osteoclast and osteoblast differentiation and function in vitro. In RANKL-induced murine osteoclast precursor cell RAW264.7 and M-CSF/RANKL-stimulated primary murine bone marrow-derived macrophages (BMM), niclosamide dose-dependently inhibited the formation of TRAP-positive multinucleated osteoclasts and resorption pits formation between 0.5uM and 1uM. In addition, niclosamide suppressed the expression of nuclear factor of activated T cells c1 (NFATc1) and osteoclast differentiated-related genes in M-CSF/ RANKLstimulated BMM by interference with TRAF-6, Erk1/2, JNK and NF-κB activation pathways. However, the cytotoxic effects of niclosamide obviously appeared at the effective concentrations for inhibiting osteoclastogenesis (0.5-1uM) with increase of apoptosis through caspase-3 activation in osteoblast precursor cell line, MC3T3-E1. Niclosamide also inhibited ALP activity, bone mineralization and osteoblast differentiation-related genes expression in MC3T3-E1. Therefore, our findings suggest the new standpoint that niclosamide's effects on bones must be considered before applying it in any therapeutic treatment.

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“…In screening a chemicall ibrary by competitive ELISA, the porphyrin verteporfin was identified as ah it. [10][11][12][13] The second approachw as to interfere with RANKL binding to RANK. [1][2][3][4][5] Osteoprotegerin (OPG),l ikewise member of the TNFreceptor superfamily,acts as an atural non-signaling decoy receptor of RANKL and thus prevents RANK activation.…”

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“…[7,8] Furthermore, the triad is involved in cancer development and metastasis. [10][11][12][13] The second approachw as to interfere with RANKL binding to RANK. Molecules such as jolkinolide Bp hytopharmaceutical, chloroquine and 5-(2',4'-difluorophenyl)salicylanilide derivatives or peptides interact with the cytoplasmic part of RANK and inhibit RANK signaling.…”

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confidence: 99%

“…Molecules such as jolkinolide Bp hytopharmaceutical, chloroquine and 5-(2',4'-difluorophenyl)salicylanilide derivatives or peptides interact with the cytoplasmic part of RANK and inhibit RANK signaling. [10][11][12][13] The second approachw as to interfere with RANKL binding to RANK. Peptidomimetics of RANK or OPG such as peptides based on the RANK loop3 sequence or on the OPG binding site of RANKL [14,15] or fusion proteins of the RANK and OPG binding domains with immunoglobulinF c were generated.…”

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Porphyrin Derivatives Inhibit the Interaction between Receptor Activator of NF‐κB and Its Ligand

et al. 2017

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Receptor activator of NF-κB (RANK), a member of the TNF-receptor superfamily, plays an important role in bone resorption and stimulates immune and epithelial cell activation. Denosumab, a human monoclonal antibody that blocks the RANK ligand (RANKL), is approved for the treatment of osteoporosis and bone metastasis. However, a small molecule that inhibits the RANK-RANKL interaction would be beneficial to decrease cost and to facilitate treatments with orally available therapeutic agents. Herein we report the discovery of the first nonpeptidic inhibitors of RANK-RANKL interactions. In screening a chemical library by competitive ELISA, the porphyrin verteporfin was identified as a hit. Derivatives were screened, and the chlorin-macrocycle-containing pheophorbide A and purpurin 18 were found to bind recombinant RANKL, to inhibit RANK-RANKL interactions in the ELISA, and to suppress the RANKL-dependent activation of model cells and the differentiation of RANK-expressing precursors into osteoclasts. This discovery of a family of small molecules that inhibit RANK activation presents an initial basis for further development of nonpeptidic therapeutic agents targeting the interaction between RANK and RANKL.

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Discovery of 5-(2′,4′-difluorophenyl)-salicylanilides as new inhibitors of receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis

Cited by 30 publications

References 48 publications

The Relationship Between Inflammatory Biomarkers and Symptom Distress in Lung Cancer Patients Undergoing Chemotherapy

The Relationship Between Inflammatory Biomarkers and Symptom Distress in Lung Cancer Patients Undergoing Chemotherapy

The Simultaneous Inhibitory Effect of Niclosamide on RANKL-Induced Osteoclast Formation and Osteoblast Differentiation

Porphyrin Derivatives Inhibit the Interaction between Receptor Activator of NF‐κB and Its Ligand

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