Inhibition of Tpl2 kinase and TNF-α production with 1,7-naphthyridine-3-carbonitriles: Synthesis and structure–activity relationships

Gavrin, Lori Krim; Green, Neal; Hu, Yonghan; Janz, Kristin; Kaila, Neelu; Li, Huan‐Qiu; Tam, Steve; Thomason, Jennifer R.; Gopalsamy, Ariamala; Ciszewski, Gregory; Cuozzo, John W.; Hall, J. Perry; Hsu, Sang; Telliez, Jean‐Baptiste; Lin, Lih-Ling

doi:10.1016/j.bmcl.2005.08.029

Cited by 49 publications

(43 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…14) This series of compounds are reported to be quite specific for Tpl2 with IC 50 of 12-50 nM. This affinity is at least 2000-to 10000-fold higher than those for other protein kinases such as Raf-1, MEK, p38, CaMKII, and so on.…”

Section: Tpl2 Inhibitor Markedly Suppresses Rankl-inducedmentioning

confidence: 88%

“…13) These results imply that Tpl2/Cot plays another role in signal transduction during osteoclast formation. Here, we examined the effects of a recently synthesized Tpl2/Cot inhibitor, 1,7-naphtyridine-3-carbonitrile, 14) on RANKL-induced osteoclast formation in the RAW264.7 cell line and M-CSF and RANKLstimulated mouse bone marrow cells. To the best of our knowledge, this is the first report showing that the MAP kinase pathway mediated via Tpl2/Cot plays an important role in RANKL-induced osteoclastogenesis from the monocyte/ macrophage lineage.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of Tumor Progression Locus 2 Protein Kinase Suppresses Receptor Activator of Nuclear Factor-.KAPPA.B Ligand-Induced Osteoclastogenesis through Down-Regulation of the c-Fos and Nuclear Factor of Activated T Cells c1 Genes

Hirata

Taki

Shinoda

et al. 2010

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Rheumatoid arthritis (RA) is characterized by the presence of inflammatory synovitis accompanied by the destruction of joint cartilage and bone.3) An increasing body of evidence has demonstrated that osteoclasts are the principal cell type responsible for bone resorption in inflammatory joint diseases. Multinucleated giant cells with the phenotypic features of osteoclasts are present at erosion sites in RA and collagen-induced arthritis animal models. Furthermore, it has been reported that mice lacking osteoclasts were resistant to arthritis-induced bone erosion. 4) These findings indicate that exploitation of chemical compounds that inhibit the generation of osteoclasts at inflammatory sites would be useful for the treatment of RA.Macrophage colony-stimulating factor (M-CSF) and receptor for activation of nuclear factor-kB ligand (RANKL) are required for osteoclastogenesis from monocytes.5,6) The binding of RANKL to its receptor RANK recruits TNF receptor associated factor 6 (TRAF6) in order to cause sequential downstream events such as the up-regulation of nuclear factor-kB (NF-kB), p38, c-Jun N-terminal kinase (JNK), extrallular signal-regulated kinase (ERK), AP-1, nuclear factor of activated T cells (NFAT)c1, which activate related genes to induce the differentiation of monocytes into osteoclasts. 6,7) Among them, NFATc1 is the most important transcription factor during osteoclastogenesis because NFATc1-deficient embryonic stem cells fail to differentiate into osteoclasts. 8,9) The expression of c-Fos, a component of AP-1, is also associated with osteoclastogenesis because c-Fos-null mice develop severe osteopetrosis due to a lack of osteoclasts, and no NFATc1 expression is seen in the osteoclast precursors of these animals.6,8) However, the mechanisms by which the cFos and NFATc1 genes are activated downstream of the RANK-TRAF6 signaling pathway triggered by RANKL have not been fully elucidated.In this study, we focused on tumor progression locus 2 (Tpl2)/cancer Osaka thyroid (Cot), which is a serine/threonine protein kinase and a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family.10,11) When Tpl2-deficient mice were treated with lipopolysaccharide (LPS), the activation of MEK and ERK, but not JNK or p38 MAP kinases or NF-kB, was abolished, resulting in decreased levels of tumor necrosis factor a (TNFa) and enhanced resistance to endotoxin shock after LPS/D-galactosamine treatments.11) Moreover, Tpl2 ablation protected the mice from TNFa-induced inflammatory bowel disease 12) and pancreatic and pulmonary inflammation.13) These results imply that Tpl2/Cot plays another role in signal transduction during osteoclast formation. Here, we examined the effects of a recently synthesized Tpl2/Cot inhibitor, 1,7-naphtyridine-3-carbonitrile, 14) on RANKL-induced osteoclast formation in the RAW264.7 cell line and M-CSF and RANKLstimulated mouse bone marrow cells. To the best of our knowledge, this is the first report showing that the MAP kinase pathway mediated via Tpl2/Cot plays an important r...

show abstract

Section: Tpl2 Inhibitor Markedly Suppresses Rankl-inducedmentioning

confidence: 88%

mentioning

confidence: 99%

Inhibition of Tumor Progression Locus 2 Protein Kinase Suppresses Receptor Activator of Nuclear Factor-.KAPPA.B Ligand-Induced Osteoclastogenesis through Down-Regulation of the c-Fos and Nuclear Factor of Activated T Cells c1 Genes

Hirata

Taki

Shinoda

et al. 2010

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

show abstract

“…Considering the contribution of endogenous Tpl2 to the activation of AP-1 and the RTA promoter, we asked if endogenous Tpl2 promotes MHV-68 lytic replication. To address this question, we used a chemical inhibitor of the Tpl2 kinase (21) in addition to the Tpl2 RNAi described above to inhibit the function of endogenous Tpl2 (Fig. 6).…”

Section: Tpl2 Enhances Mhv-68 Lytic Replicationmentioning

confidence: 99%

Tpl2/AP-1 Enhances Murine Gammaherpesvirus 68 Lytic Replication

Feng

Chen

et al. 2010

J Virol

View full text Add to dashboard Cite

“…These classes of compounds will be discussed below. Gavrin et al, (2005) first described a series of 6-substituted-4-anilino-[1,7]-naphthyridine-3-carbonitriles as Tpl2 inhibitors evaluated in cell-free, cellular, and blood environments. One of these compounds, 1,7-naphtyridine-3-carbonitrile, was used successfully to inhibit RANKL-induced osteogenesis through the induction of transcription factors c-Fos and NFATc1 in RANKL treated cells, unraveling the pivotal role played by Tpl2 in osteoclastogenesis .…”

Section: Tpl2 Inhibitorsmentioning

confidence: 99%