Fimepinostat (CUDC 907) is an orally bioavailable inhibitor of both phosphoinositide 3-kinase (PI3K) class I and pan-histone deacetylase (HDAC) enzymes, with potential antineoplastic activity. Upon oral administration, CUDC-907 inhibits the activity of both PI3K class I isoforms and HDAC, thereby preventing the activation of the PI3K-AKT-mTOR signal transduction pathway that is often overactivated in many cancer cell types.

HDAC10:2.8 nM, HDAC11:5.4 nM, HDAC3:1.8 nM, HDAC2:5.0 nM, HDAC1:1.7 nM

在作用于NHL和MM模型的高效性研究中, CUDC-907按最大耐受剂量处理,比单独药剂PI3K或HDAC抑制剂或两者联用效果更明显.且按最大耐受剂量处理,CUDC-907比PI3Kδ选择性抑制剂CAL-101更有效.CUDC-907对犬类具有口服生物有效性.CUDC-907在小鼠肿瘤中的半衰期较长.作用于移植瘤时,CUDC-907诱导凋亡并抑制癌细胞增殖.

CUDC-907对一系列B细胞淋巴瘤的生长具有抑制作用,如Granta 519（IC50：7 nM）,DOHH2（IC50：1 nM）,RL（IC50：2 nM）,Pfeiffer（IC50：4 nM）,SuDHL4（IC50：3 nM）,Daudi（IC50：15 nM） 和 Raji（IC50：9 nM）。CUDC-907对骨髓瘤增殖也有阻断作用,如RPMI8226（IC50：2 nM）,OPM-2（IC50：1 nM）和ARH77（IC50：5 nM）。CUDC-907对多发性骨髓瘤和B细胞淋巴瘤均有明显抗癌活性。CUDC-907对其他PI3K亚型有抑制作用抑制,如 PI3Kβ/γ/δ和 PI3KαE545K, IC50分别为 54/311/39/62 nM。而且, CUDC-907对HDAC亚型HDAC8//6/11（IC50：191/27/5.4 nM）也有抑制效果。此外,CUDC-907对其他类型 HDAC 酶活性也有微弱抑制。

The activities of classes I and II HDACs are measured using the Color-de-Lys assay system. The activity of PI3K is measured using the ADP-Glo luminescent kinase assay. Recombinant PI3K protein, a complex of N-terminal GST-tagged recombinant full-length human p110 and untagged recombinant full-length human p85, is coexpressed in a baculovirus-infected Sf9 cell expression system[1].

CUDC-907 is dissolved in DMSO and stored (-80°C), and then diluted with appropriate medium before use[1]. Human cancer cell lines are plated at densities of 5,000 to 10,000 per well in 96-well flat-bottomed plates with the recommended culture medium. The cells are then incubated with compounds (e.g.,CUDC-907) at various concentrations for 72 hours in culture medium supplemented with 0.5% (v/v) FBS. Growth inhibition is assessed by assay of cellular ATP content using the Perkin-Elmer ATPlite kit[1].