tcsc0079 BX-912

BX-912 is a potent PDK1 inhibitors with an IC₅₀ of 12 nM.

IC50 & Target: IC50: 12 nM (PDK1), 110 nM (PKA), 410 nM (KDR), 650 nM (CDK2/cyclin E), 830 nM (Chck1), 850 nM (c-Kit), 1.25 μM (PKC), 2.1 μM (T-Fyn), 6.1 μM (Insulin receptor), 7.4 μM (GSK3β)^[1]

In Vitro: BX-912 also inhibits PKA, KDR, CDK2/cyclin E, Chck1, c-Kit, PKC, T-Fyn, Insulin receptor, and GSK3β with IC₅₀s of 110 nM, 410 nM, 650 nM, 830 nM, 850 nM, 1.25 μM, 2.1 μM, 6.1 μM and 7.4 μM in kinase assays, respectively. BX-912 is identified in a coupled assay measuring PDK1- and PtdIns-3,4-P₂-mediated Akt activation, which can detect inhibitors of PDK1, AKT2, or other steps critical for activation of AKT2. BX-912 potently inhibits PDK1 enzyme activity in a direct kinase assay format (IC₅₀=26), although BX-912 fails to block preactivated AKT2 activity (IC₅₀>10 μM). BX-912 binds to the ATP binding site of PDK1. The aminopyrimidine backbone of BX-912 adopts a similar orientation in the active site of PDK1. To examine the kinase selectivity of BX-912, its effects on the in vitro activity of 10 different Ser/Thr and tyrosine kinases are determined, including the related AGC kinases PKA and PKCα. BX-912 is 9-fold selective for PDK1 relative to PKA. BX-912 blocks PDK1 activity in PTEN-negative PC-3 cells. PTEN-negative PC-3 cells display constitutive activation of Akt which is reflected in high levels of the PDK1 product, phospho-Thr³⁰⁸-Akt^[1].