PomalIDOmide 是一种抗血管生成剂和免疫调节剂，以分子胶的方式作用。它与 E3 连接酶 cereblon 相互作用，诱导必需的 IkaROS 转录因子的降解。

Pomalidomide inhibits TNF-α release in LPS stimulated human PBMCs (IC50: 13 nM). It is an anti-angiogenic agent and an immunomodulator.

Pomalidomide (CC-4047) was significant inhibition against TNFα in Human PBMC cell with an IC50 of 13 nM [1]. Pomalidomide inhibits IL-2-mediated generation of FOXP3 positive CTLA-4 positive CD25high CD4+ T regulatory cells from PBMCs by up to 50% [2]. Exposure of lymphoma cells to CC-4047 resulted in a lesser degree of growth inhibition. Induction of apoptosis was shown in 10% to 26% of lymphoma cells 24 hours following exposure to CC-4047 [3].

In vivo studies in severe combined immunodeficient mice showed synergistic activity between CC-4047 plus rituximab. Animals treated with the CC-4047/rituximab combination had a median survival of 74 days [3]. POM has desirable pharmacokinetic properties in the rat. It had relatively slow clearance (12.3 mL/min/kg), a reasonable volume of distribution (1.75 L/kg), and an acceptable bioavailability (47.4%). Following a 50 mg/kg PO administration of POM to rats, unbound concentrations in blood reached a Cmax value of 1100 ± 82 ng/mL at 4.6 ± 2.4 hours, with a concomitant AUC(0?10) value of 6800 ± 2000 ng·hr/mL [4].

TNF-α inhibitory activity is measured in lipopolysacharide (LPS) stimulated PBMC. Pomalidomide is added to human PBMCs 1 hour prior to the addition of LPS (1 μg/mL) and incubation continued for an additional 18-20 hours. Supernatants are then harvested, and the concentration of TNF-α in the supernatants is determined by ELISA. The concentration of Pomalidomide that IC50 is calculated by nonlinear regression analysis [1].

In vitro effects of either CC-5013 or CC-4047 as single agent or in combination with rituximab were evaluated by flow cytometric analysis. Lymphoma cell lines (1 × 10^6 cells) were exposed to either CC-5013 (5 μg/mL), CC-4047 (5 μg/mL), or vehicle control (DMRIE-C, 0.01%) alone or in combination with rituximab at a final concentration of 10 μg/mL. Following a period of incubation of 24 or 48 hours, apoptosis was assessed by staining-treated cells with FITC-labeled Annexin V and propidium iodine. All samples were analyzed by multicolor flow cytometric analysis using a fluorescence-activated cell sorter/FACStar Plus flow cytometer. Cells were scored as apoptotic if they were Annexin V–positive and propidium iodine–negative/positive (early and late apoptosis, respectively) [2].

These studies were carried out using a disseminated lymphoma-bearing SCID mouse xenograft model. Raji cells were harvested from confluent cultures and only suspensions with >90% viable cells were used for animal inoculation. Subsequently, on day 0, SCID mice received 1 ×10^6 Raji cells via i.v. Untreated SCID mice inoculated by i.v. injection develop symptomatic central nervous system, pulmonary, and liver metastasis that result in death from massive tumor burden and central nervous system involvement after 17 to 21 days after inoculation. A second lymphoma mouse model was used to address the significance of NK cell expansion in the biological interactions observed between rituximab and IMiDs. The second mouse lymphoma xenograft consisted of SCID mice depleted of NK cells bearing Raji cells implanted via tail vein injection as described above [2].

19171-19-8

C13H11N3O4

273.248

泊马度胺;CC-4047

H2O:<1 mgml
Ethanol:<1 mgml
DMSO:54 mg/mL (197.63 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years