KINK-1 HYDROCHLORIDE

Biochem/physiol Actions

KINK-1 (Kinase Inhibitor of NF-κB-1; Bay 65-1942; CmpdA; Compound A) is an ATP-competitive, IKKβ-selective IκB kinase (IKK) inhibitor (Ki against ATP = 2 nM/IKKβ and 135 nM/IKKα) that potently inhibits IKKβ-catalyzed GST-IκBα(1–54) phosphorylation (IC50 = 4 nM, 200 nM ATP) without affecting (IC50 >10µM) IKK3 or 27 other kinases, lipases, phosphatases, caspases, and MMPs. KINK-1 effectively inhibits NF-κB activation and cytokines production in various human and murine cultures (IC50 from 18 to 502 nM) and is efficacious against LPS-induced plasma TNF-α production in mice and rats in vivo (EC50 = 9.1 and 6.6 mg/kg p.o., repectively) with good pharmacokinetic profile and oral availability. KINK-1 is also shown to effectively inhibit OVA-induced lung inflammation in a rat model of asthma (ED50 ﹤0.3 mg/kg p.o.) without adverse effects to the animals.