N-(6-CHLORO-9H-PYRIDO[3,4-B]INDOL-8-YL)-3-PYRIDINECARBOXAMIDE DIHYDROCHLORIDE

Uses

N-(6-Chloro-9H-pyrido[3,4-b]indol-8-yl)-3-pyridinecarboxamide is an inhibitor of IKKβ, an enzyme involved with the cytokine-activated intracellular signaling pathway that regulates the immune response. N-(6-Chloro-9H-pyrido[3,4-b]indol-8-yl)-3-pyridinecarboxamide also inhibits osteoclast differentiation.

Uses

PS-1145 dihydrochloride has been used as an IκB kinase (IKK) inhibitor:

• in the culture medium to treat human epidermal keratinocytes (HEKs) and squamous carcinoma cells (SCCs) to study the role of IKK in?Corynebacterium tuberculostearicum?(C. t.)-elicited transcription of inflammatory mediators
• to investigate the involvement of transcription factor p65 (RelA)/nuclear factor kappa-B (NF-κB) in the cluster of differentiation 28 (CD28)-mediated interleukin-17A (IL-17A) gene expression
• to examine the involvement of NF-κB signaling in the cytotoxic effect of niclosamide on colorectal cancer (CRC) cells

Definition

ChEBI: N-(6-chloro-9H-pyrido[3,4-b]indol-8-yl)-3-pyridinecarboxamide is a member of beta-carbolines.

Biological Activity

ps-1145 is an ikappab kinase (ikk) inhibitor.the iκb kinase is an enzyme complex involved in propagating the cellular response to inflammation. this enzyme complex is reported to be part of the upstream nf-κb signal transduction cascade.

Biochem/physiol Actions

PS-1145, a β-carboline derivative, blocks the phosphorylation and degradation of the inhibitor of nuclear factor kappa-β (NF-κB;). It also inhibits the subsequent activation of nuclear factor kappa-β (NF-κB) and thereby prevents the release of tumor necrosis factor-α (TNF-α) in lipopolysaccharide treated mice. PS-1145 hinders pro-inflammatory cytokine production and cell proliferation. It plays a potential therapeutic role in carcinogenesis in multiple myeloma. PS-1145 exhibits anti-tumor activity on nasopharyngeal carcinoma (NPC) cell lines.

in vitro

previous study found that ps-1145 could block tnfalpha-induced nf-kappab activation in a dose- and time-dependent manner in mm cells, which up-regulated ikappabalpha protein, enhanced blockade of nf-kappab activation. in addition, ps-1145 blocked the protective effect of il-6 against dex-induced apotosis and tnfalpha-induced icam-1 expression was also inhibited by ps-1145. moreover, ps-1145 inhibited both il-6 secretion from bmscs triggered by mm cell adhesion and proliferation of mm cells adherent to bmscs. however, ps-1145 could only partially inhibit mm cell proliferation. importantly, it was found that tnfalpha induced mm cell toxicity in the presence of ps-1145 [1]

in vivo

animal study showed that the intravenous application of ps-1145 could promote direct apoptosis in dmba-induced skin tumor in male wistar rats via blocking nf-κb and vegf activities [2].

IC 50

88 nm

References

[1] hideshima t,chauhan d,richardson p,mitsiades c,mitsiades n,hayashi t,munshi n,dang l,castro a,palombella v,adams j,anderson kc. nf-kappa b as a therapeutic target in multiple myeloma. j biol chem.2002 may 10;277(19):16639-47.
[2] rajmani rs,gandham rk,gupta sk,et al. administration of iκb-kinase inhibitor ps1145 enhances apoptosis in dmba-induced tumor in male wistar rats. cell biol int.2015 nov;39(11):1317-28.