IC50: 8.5 and 250 nM for IKKβ and IKKα, respectively
ACHP is an IκB kinase inhibitor. Nuclear factor-KB (NF-KB) involved in cell survival and proliferation of multiple myeloma has been well established.
In vitro: 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.
In vivo: So far, no study in vivo has been conducted.
Clinical trial: Clinical study has been conducted.
Reference:
[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.