SC-514 is a selective and reversible inhibitor of IκB kinase 2 (IKK2) that may target osteoclastogenesis. SC-514 dose-dependently inhibits RANKL-induced osteoclastogenesis and induced apoptosis and caspase 3 activation in RAW264.7 cells. Targeting IKKβ by SC-514 may be a potential treatment for osteoclast-related disorders such as osteoporosis and cancer-induced bone loss.
Chemical Formula: C9H8N2OS2
Exact Mass: 224.0078
Molecular Weight: 224.296
Elemental Analysis: C, 48.19; H, 3.60; N, 12.49; O, 7.13; S, 28.59
InChi Code: InChI=1S/C9H8N2OS2/c10-6-3-7(5-1-2-13-4-5)14-8(6)9(11)12/h1-4H,10H2,(H2,11,12)
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
SC-514 inhibits the native IKK complex or recombinant human IKK-1/IKK-2 heterodimer with IC50s of 6.1±2.2 μM and 2.7±0.7 μM, respectively. IKK-2 inhibition by SC-514 is selective, reversible, and competitive with ATP. SC-514 inhibits transcription of NF-κB-dependent genes in IL-1β-induced rheumatoid arthritis-derived synovial fibroblasts in a dose-dependent manner. SC-514 inhibits all forms of recombinant human IKK-2 including rhIKK-2 homodimer, rhIKK-1/rhIKK-2 heterodimer, as well as the constitutively active form of rhIKK-2 with comparable IC50 values in the 3-12 μM range. To evaluate whether the reactive oxygen species (ROS)-inducing IKKβ inhibitor increases the sensitivity of melanoma cells to nitrosourea. The responses of melanoma cells are first assessed to SC-514/Fotemustine co-treatment. Melanoma cell lines are treated with 50 µM of SC-514 and Fotemustine alone and in combination for 48 h and growth inhibition is assessed. Co-treatment with SC-514 significantly enhances Fotemustine-induced cytotoxicity in all melanoma cell lines tested.
SC-514 is efficacious in an acute model of inflammation, namely LPS-induced serum TNFα production in the rat. SC-514 shows a dose-dependent inhibition of TNFα production, validating IKK-2 as a potential anti-inflammatory drug target in vivo. To obtain in vivo evidence for the implication of SC-514 in the response of cancer cells to Fotemustine, the xenograft mouse model of melanoma is used. Nude mice engrafted with A375 or G361 tumors are treated with vehicle control and 25 mg/kg SC-514 and/or 25 mg/kg Fotemustine daily for 13-15 consecutive days and the tumor behavior is monitored. Fotemustine treatment with SC-514 shows a clear combined effect and reduces the size of tumors in mice.
Kishore, N., Sommers, C., Mathialagan, S., et al. A selective IKK-2 inhibitor blocks NF- k B-dependent gene expression in interleukin-1ß-stimulated synovial fibroblasts. The Journal of Biological Chemisty 278(35), 32861-32871 (2003).
Baxter, A., Brough, S., Cooper, A., et al. Hit-to-lead studies: The discovery of potent, orally active, thiophenecarboxamide IKK-2 inhibitors. Bioorganic & Medicinal Chemistry Letters 14, 2817-2822 (2004).
Gomez, A.B., MacKenzie, C., Paul, A., et al. Selective inhibition of inhibitory kappa B kinase-b abrogates induction of nitric oxide synthase in lipopolysaccharide-stimulated rat aortic smooth muscle cells. British Journal of Pharmacology 146, 217-225 (2005).
Phulwani, N.K., Esen, N., Syed, M.M., et al. TLR2 expression in astrocytes is induced by TNF-α-and NF- k B-dependent pathways. Journal of Immunology 181, 3841-3849 (2008).
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