tcsc0283 ACHP (Hydrochloride)

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

IC50 & Target: IC50: 8.5 nM (IKK-β), 250 nM (IKK-α), >20000 nM (IKK3, Syk and MKK4)^[1]

In Vitro: ACHP (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). Moreover, ACHP demonstrates quite potent activity in various cellular assays. 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].

In Vivo: ACHP (Compound 4j) 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 (P_app 62.3×10^-7 cm/s), and demonstrates orally bioavailability in mice (BA: 16%) and rats (BA: 60%). The favourable 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].