CCF642 (AC1LYELL) is a novel PDI-inhibiting compound with antimyeloma activity.

PDI:2.9 μmol/L

在体外实验中，CCF642 抑制 PDI 还原酶的活性比结构不同的已知抑制剂 PACMA 31 和 LOC14 高出约100倍。计算模型预测，CCF642 通过与活性位点 CGHCK 模体的共价结合方式产生作用。CCF642 在多发性骨髓瘤细胞中引起急性内质网应激，并伴随着促进凋亡的钙释放[1]。

CCF642 在一种侵袭性的同源小鼠多发性骨髓瘤模型中展现出了强大的疗效，并且能延长植入5TGM1-luc骨髓瘤的C57BL/KaLwRij小鼠的寿命，该效果与一线多发性骨髓瘤治疗化合物博腾尼布[1]相当。

Inhibition of CB-839 on rHu-GAC: The enzymatic activity is measured in assay buffer containing 50 mM Tris-Acetate pH 8.6, 150 mM K2HPO4 , 0.25 mM EDTA, 0.1 mg/mL bovine serum albumin, 1 mM DTT, 2 mM NADP+ and 0.01% Triton X-100. To measure inhibition, the inhibitor (prepared in DMSO) is first pre-mixed with glutamine and glutamate dehydrogenase (GDH) and reactions are initiated by the addition of rHu-GAC. Final reactions contains 2 nM rHu-GAC, 10 mM glutamine, 6 units/mL GDH and 2% DMSO. Generation of NADPH is monitored by fluorescence (Ex340/Em460 nm) every minute for 15 minutes on a SpectraMax M5e plate reader. Relative fluorescence units (RFU) are converted to units of NADPH concentration (μM) using a standard curve of NADPH. Each assay plate incorporates control reactions that monitores the conversion of glutamate (1 to 75 μM) plus NADP+ to α-ketoglutarate plus NADPH by GDH. Under these assay conditions, up to 75 μM glutamate is stoichiometrically converts to α-ketoglutarate/NADPH by GDH. Initial reaction velocities are calculated by fitting the first 5 minutes of each progress curve to a straight line. Inhibition curves are fitted to a four-parameter dose response equation of the form: % activity = Bottom + (Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)).