ACHP is an IkB kinase inhibitor, which has dose-dependently inhibited cell growth with inhibition of phosphorylation of IκBα/p65 and NF-κB DNA-binding, down-regulation of NF-κB target genes and induced apoptosis in human myeloma cell lines.
ChEBI: 2-amino-6-[2-(cyclopropylmethoxy)-6-oxo-1-cyclohexa-2,4-dienylidene]-4-(4-piperidinyl)-1H-pyridine-3-carbonitrile is a member of quinomethanes.
achp is an iκb kinase inhibitor. nuclear factor-kb (nf-kb) involved in cell survival and proliferation of multiple myeloma has been well established.
achp is selective for ikkα and ikkβ over ikk3, syk and mapkkk4 (ic50 > 20 μm), dna binding activity of nf-κb is inhibited. achp is an effective blockade nf-κb pathway in multiple myeloma cell lines, and induces cell growth arrest and apoptosis. it was observed that nf-kb is constitutively activated in all human myeloma cell lines, thus confirming the previous studies. in addition, it was found the phosphorylation of p65 subunit of nf-kb besides the phosphorylation of ikba and the activation of nf-kb dna binding and that various target genes of nf-kb including bcl-xl, xiap, c-iap1, cyclin d1, and il-6 are up-regulated. 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinenitrile (achp) is a novel ikb kinase inhibitor. treatment of myeloma cells with achp showed the cell growth was efficiently inhibited (ic50 values ranging from 18 to 35 mmol/l) concomitantly with inhibition of the phosphorylation of ikba/p65 and nf-kb dna-binding, down-regulation of the nf-kb target genes, and then induction of apoptosis. in addition, the treatment of achp potentiated the cytotoxic effects of vincristine and melphalan (l-phenylalanine mustard), conventional antimyeloma drugs. these findings suggest that by blocking the antiapoptotic nature of myeloma cells endowed by the constitutive activation of nf-kb, ikb kinase inhibitors such as achp can sensitize myeloma cells to the cytotoxic effects of chemotherapeutic agents.
This novel IKK inhibitor (FW = 364.44 g/mol; CAS 406208-42-2; Soluble to 20 mM in DMSO), also named 2-amino-6-[2-(cyclopropylmethoxy)-6hydroxyphenyl]-4-(4-piperidinyl)-3-pyridinecarbonitrile, targets IκB kinases, with respective IC50 values of 8.5 and 250 nM for IKKβ and IKKα. ACHP’s selectivity is indicated by its > 20-μM IC50 values toward IKK3, Syk, and MAPKKK4. Inhibition of the TNFα-mediated gene expression could occur at low ACHP concentration (<1 μmol/L), with higher concentrations (>10 μmol/L) required to inhibit the constitutive phosphorylation of p65, expression of NF-κB-mediated genes (e.g., CYCLIN D1, BCL-xL, XIAP, c-IAP1, and IL-6), ultimately achieving myeloma cytostasis. Such findings indicate that ACHP’s growth inhibitory effects may be mediated through inhibition of both IKKα and IKKβ. By inhibiting NF-κB’s DNA binding activity, ACHP blocks the NF-κB pathway in multiple myeloma cell lines, inducing growth arrest and apoptosis.
8.5 and 250 nm for ikkβ and ikkα, respectively
[1] sanda t, iida s, ogura h, asamitsu k, murata t, bacon kb, ueda r, okamoto t. growth inhibition of multiple myeloma cells by a novel ikappab kinase inhibitor. clin cancer res. 2005 mar 1;11(5):1974-82.
