BMS-066 is an IKKβ/Tyk2 pseudokinase inhibitor with IC50s of 9 nM and 72 nM, respectively.

TYK2:72 nM, IKKβ:9 nM

BMS-066 demonstrates significant inhibition of IKKβ-catalyzed phosphorylation in vitro, with a potent IC50 of 9 nM, exhibiting over 500-fold selectivity towards IKKβ compared to IKKα. In assays with six kinases that were more than 75% inhibited at 10 μM, BMS-066 displayed over 30-fold selectivity over the next most susceptible kinase (Brk), indicating its specificity. Additionally, BMS-066 showed IC50 values of 72 and 1020 nM in Tyk2 pseudokinase domain probe displacement and IL-23-stimulated reporter assays respectively. A broader selectivity assessment against 155 kinases at 10 μM revealed that only six were inhibited more than 75%, confirming BMS-066's greater than 400-fold selectivity for IKKβ over 95% of the kinases tested. BMS-066 also effectively inhibits LPS-stimulated cytokine production in human peripheral blood mononuclear cells (PBMCs) at both protein and mRNA levels, with similar IC50 values around 200 nM, and it inhibits IKKβ-mediated phosphorylation of IkBα in LPS-stimulated cells with a comparable efficacy.

Clear reduction of inflammation is also evident in the low dose of BMS-066 (5 mg/kg) and the bone resorption seems to be more focal and less severe compared with the control. The joints from animals receiving 10 mg/kg BMS-066 are normal or show minimal changes in both inflammation and bone resorption. Bone density measurements also show a clear dose-dependent benefit of treatment with BMS-066. Microcomputed tomography of the hind limbs also show that BMS-066 provides a dose-dependent protection against the pitting, loss of bone mass, woven porous bone, and fusion of the small bones evident in the rats. Serum drug level measurements in satellite animals on the first day of dosing show that a single dose provides coverage for approximately 3 h (6 h daily with twice daily dosing) of the mouse whole-blood IC50 value against LPS-induced TNF-α. It is also showed that IKKβ inhibitors suppress TNF-α and IL-1β production within these tissues in experimental arthritis model[1].