ACHP Hydrochloride 是选择性的IKK-β抑制剂 (IC50=5.8 nM)。

ACHP Hydrochloride is a highly potent and selective IKK-β inhibitor with an IC50 of 8.5 nM.

ACHP Hydrochloride (Compound 4j) exhibits potent IKK-β inhibitory (IC50: 8.5 nM) and cellular activities (IC50: 40 nM, in A549 cells). ACHP moderately inhibits IKK-α with an IC50 of 250 nM but exhibits good selectivity towards other kinases, such as IKK3, Syk, and MKK4 (IC50>20,000 nM). ACHP inhibits NF-κB-dependent reporter gene activation in TNFα-activated HEK293 cells and PMA/calcium ionophore-activated Jurkat T cells. ACHP fails to inhibit PMA-induced AP-1 activation in MRC-5 cells and PMA/calcium ionophore induced NF-κB dependent reporter gene transcription in Jurkat cells even at concentrations exceeding 10 μM. ACHP selectively interferes with the NF-κB signaling cascade by inhibition of IKK-β in living cells [1]. ACHP inhibits the growth of these cells in a dose-dependent manner. Tax-active cell lines are more susceptible to ACHP than Tax-inactive cell lines and Jurkat (IC50 values in Tax-active cell lines, Tax-inactive cell lines or Jurkat are 3.1±1.3?μM, 10.7±1.7?μM and 23.6?μM, respectively), suggesting that the growth of Tax-active cells depends on NF-κB more than Tax-inactive cells [2].

ACHP is orally bioavailable in mice and rats and demonstrates significant in vivo activity in anti-inflammatory models (arachidonic acid-induced mouse ear edema model). ACHP has reasonable aqueous solubility (0.12 mg/mL in pH 7.4 isotonic buffer) and excellent Caco-2 permeability (Papp 62.3×10^-7 cm/s), and demonstrates orally bioavailability in mice (BA: 16%) and rats (BA: 60%). The favorable bioavailability of ACHP in rats is likely due to its low clearance (0.33 L/h/kg). In an acute inflammation model, ACHP exhibits oral efficacy at 1 mg/kg in a dose-dependent manner [1].

HTLV-1-infected T-cell lines, ATL-35T, 81-66/45, MJ, and MT-2 cells, human ATL cell lines established from ATL patients, ATL-102, ED-40515(?) and TL-Om1 cells, and an HTLV-1-negative T-cell leukemia cell line Jurkat are used in this study. Approximately 1.5×10^4 cells are cultured in 96-well plates in triplicates at 37°C. Growth inhibitory effect of ACHP (0.01, 0.1, 1, 5, 10, 50 and 100 μM) is determined using MTT assay. Optical densities (OD) at 570 and 630?nm are measured with a multi-plate reader. Cell viability (%) is calculated [2].

In vivo arachidonic acid-induced ear edema in mice: ear edema is induced by topical application of arachidonic acid (500 μg/ear). ACHP (0.3, 1 and 3 mg/kg, p.o.), Dexamethasone, and vehicle (10% cremophor in saline) are given po 60 min before the arachidonic acid application. Ear thickness is measured at 0, 1, 3, and 6 h after the arachidonic acid application [1].

406209-26-5

C21H25ClN4O2

400.9

IKK-2 Inhibitor VIII

DMSO:45 mg/mL (112.25 mM),Need ultrasonic
Powder: -20°C for 3 years
In solvent: -80°C for 2 years