CUDC-907
(Synonyms: CUDC-907) 目录号 : GC12115
CUDC 是一种口服生物可利用的小分子 PI3K 和 HDAC 双重抑制剂，作用于 PI3K α 和 HDAC1 / 2 / 3 / 10，IC50 分别为 19 nm 和 1.7 nm / 5 nm / 1.8 nm / 2.8 nm .在 WSU DLCL2 细胞中评估了双功能 HDAC 和 PI3K 抑制剂 CUDC-907 的抗肿瘤活性。
Cas No.:1339928-25-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
keloid fibroblasts (KFs) |
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Preparation Method |
The KFs from the secondary culture were seeded onto 96-well plates at a density of 1000 cells/well. Starved cells were treated with medium containing the CUDC-907, GDC-0941 and trichostatin A. Cell proliferation was examined using Cell Counting Kit-8 according to the manufacturer's protocol. |
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Reaction Conditions |
0.32nM 3.2nM 32nM 1、3 、5 、7days |
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Applications |
CUDC-907 significantly decreased the proliferation of KFs in a dose-dependent manner. In addition, the dual inhibitor CUDC-907 was markedly more potent compared with GDC-0941, a PI3K/Akt/mTOR inhibitor, and trichostatin A, a HDAC inhibitor, following drug treatment for 7 days. |
| Animal experiment [2]: | |
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Animal models |
C57BL mice |
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Preparation Method |
When the tumor volume reached about 100mm3 in about 2 to 3 weeks, the mice were randomized into four groups and treated with DMSO control, CUDC-907, olaparib, and CUDC-907/olaparib combination for 15 days. For drug treatment, CUDC-907 was administrated to mice by oral gavage at a dose of 75 mg/kg/day. Olaparib was administrated to mice by intraperitoneal administration at a dose of 55 mg/kg/day. The tumor volume and weight of mice were measured every 3 days. Tumor sizes were measured using a caliper. Tumor weights were measured after 15 days of drug treatment. |
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Dosage form |
75 mg/kg/day |
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Applications |
No significant difference in body weight between control and treated mice was observed, indicating that CUDC-907 monotherapy or in combination with olaparib is well tolerated. While olaparib as monotherapy showed limited efficacy, CUDC-907-treated mice exhibited more potent tumor growth inhibition than vehicle-treated mice. Remarkably, the combination of CUDC-907 and olaparib resulted in a more robust antitumor efficacy in tumor-bearing mice than either single-agent treatment group. |
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References: [1]. Tu T, Huang J, Lin M, et al. CUDC‑907 reverses pathological phenotype of keloid fibroblasts in vitro and in vivo via dual inhibition of PI3K/Akt/mTOR signaling and HDAC2[J]. International journal of molecular medicine, 2019, 44(5): 1789-1800. [2]. Ma L, Bian X, Lin W. The dual HDAC-PI3K inhibitor CUDC-907 displays single-agent activity and synergizes with PARP inhibitor olaparib in small cell lung cancer[J]. Journal of Experimental & Clinical Cancer Research, 2020, 39(1): 1-14. |
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CUDC is an orally bioavailable small molecule PI3K and HDAC dual inhibitor that acts on PI3K α And HDAC1 / 2 / 3 / 10 with IC50 of 19 nm and 1.7 nm / 5 nm / 1.8 nm / 2.8 nm [1].
The antitumor activity of the dual function HDAC and PI3K inhibitor CUDC-907 in WSU DLCL2 cells were evaluated. It was observed that CUDC-907 inhibits cell growth and induces apoptosis with nanomolar potency. The cell cycle arrest at G2/M phase, while the expression of cyclin dependent kinase inhibitor 1 was enhanced and the expression of cyclin B was decreased when the cells treated with CUDC-907. CUDC-907 can not only inhibit the phosphorylation of Akt and mTOR and promote the acetylation of histone H3, but also significantly inhibit the phosphorylation levels of Smad2 / 3 and ERK. CUDC-907 may be a candidate drug for the treatment of systemic keloid [2]. CUDC-907 treatment downregulated MYC paralogs and FoxM1, induced G1 cell cycle arrest, and impaired the DNA double strand break (DSB) repair ability of SCLC cells, resulting in an effective antiproliferative effect. In addition, It was found that CUDC-907 treatment enhanced the therapeutic effect of the PARP inhibitor olaparib in SCLC cell models and PDX models. Mechanistic studies showed that cudc-907 synergized with olaparib by blocking the DSB repair pathway and downregulating myc paralogs and FoxM1 [3].
Human pancreatic xenograft model was established by subcutaneous injection of human pancreatic cancer Aspc-1 cells into nude mice. After 19 days of gavage, the tumor growth of Aspc-1 xenograft mice treated with 300 mg / kg cudc-907 once a day was significantly reduced compared with the vehicle group, with a T / C (%) of 43.9% (P ? < 0.01). Importantly, there was no weight loss [4]. It was evaluated that the in vivo role of clinical grade cudc-907 in a mouse model of fibrosis that recapitulates the clinical behavior of idiopathic pulmonary fibrosis. After intratracheal injection of bleomycin, mice were treated with 35% captisol (control) or 1 mg / kg CUDC-907 dissolved in 35% captisol. We found that cudc-907 treatment inhibited collagen accumulation. On day 18, these mice exhibited a significant attenuation of bleomycin induced total lung collagen deposition. In addition, immunohistochemical staining of left lung sections showed that cudc-907 treatment inhibited bleomycin induced total col1, col3 and α- SMA [5].
References:
[1] Whitfield J R, Beaulieu M E, Soucek L. Strategies to inhibit Myc and their clinical applicability[J]. Frontiers in cell and developmental biology, 2017, 5: 10.
[2] Tu T, Huang J, Lin M, et al. CUDC_x001E_907 reverses pathological phenotype of keloid fibroblasts in vitro and in vivo via dual inhibition of PI3K/Akt/mTOR signaling and HDAC2[J]. International journal of molecular medicine, 2019, 44(5): 1789-1800.
[3] Ma L, Bian X, Lin W. The dual HDAC-PI3K inhibitor CUDC-907 displays single-agent activity and synergizes with PARP inhibitor olaparib in small cell lung cancer[J]. Journal of Experimental & Clinical Cancer Research, 2020, 39(1): 1-14.
[4] Fu X, Zhang X, Yang H, et al. CUDC-907 displays potent antitumor activity against human pancreatic adenocarcinoma in vitro and in vivo through inhibition of HDAC6 to downregulate c-Myc expression[J]. Acta Pharmacologica Sinica, 2019, 40(5): 677-688.
[5] Zhang W, Zhang Y, Tu T, et al. Dual inhibition of HDAC and tyrosine kinase signaling pathways with CUDC-907 attenuates TGFβ1 induced lung and tumor fibrosis[J]. Cell death & disease, 2020, 11(9): 1-13.
CUDC 是一种口服生物可利用的小分子 PI3K 和 HDAC 双重抑制剂,作用于 PI3K α 和 HDAC1 / 2 / 3 / 10,IC50 分别为 19 nm 和 1.7 nm / 5 nm / 1.8 nm / 2.8 nm [1 ].
在 WSU DLCL2 细胞中评估了双功能 HDAC 和 PI3K 抑制剂 CUDC-907 的抗肿瘤活性。据观察,CUDC-907 以纳摩尔效力抑制细胞生长并诱导细胞凋亡。 CUDC-907处理后细胞周期停滞在G2/M期,细胞周期蛋白依赖性激酶抑制剂1表达增强,细胞周期蛋白B表达降低。 CUDC-907 不仅可以抑制 Akt 和 mTOR 的磷酸化,促进组蛋白 H3 的乙酰化,还可以显着抑制 Smad2/3 和 ERK 的磷酸化水平。 CUDC-907可能是治疗系统性瘢痕疙瘩的候选药物[2]。 CUDC-907 治疗下调 MYC 旁系同源物和 FoxM1,诱导 G1 细胞周期停滞,并损害 SCLC 细胞的 DNA 双链断裂 (DSB) 修复能力,从而产生有效的抗增殖作用。此外,还发现CUDC-907治疗增强了PARP抑制剂奥拉帕尼在SCLC细胞模型和PDX模型中的治疗效果。机制研究表明,cudc-907 通过阻断 DSB 修复途径并下调 myc paralogs 和 FoxM1 [3] 与奥拉帕尼协同作用。
通过将人胰腺癌Aspc-1细胞皮下注射到裸鼠体内,建立人胰腺异种移植模型。灌胃 19 天后,每天一次 300 mg/kg cudc-907 处理的 Aspc-1 异种移植小鼠的肿瘤生长与载体组相比显着降低,T/C (%) 为 43.9% (P 〉 < ；0.01）。重要的是,体重没有减轻[4]。评估了临床级 cudc-907 在纤维化小鼠模型中的体内作用,该模型概括了特发性肺纤维化的临床行为。气管内注射博来霉素后,用 35% captisol（对照）或溶解在 35% captisol 中的 1 mg/kg CUDC-907 处理小鼠。我们发现 cudc-907 处理抑制了胶原蛋白的积累。在第 18 天,这些小鼠表现出博来霉素诱导的总肺胶原沉积的显着减弱。此外,左肺切片的免疫组织化学染色显示,cudc-907 处理可抑制博来霉素诱导的总 col1、col3 和 α-SMA [5]。
| Cas No. | 1339928-25-4 | SDF | |
| 别名 | CUDC-907 | ||
| 化学名 | N-hydroxy-2-[[2-(6-methoxypyridin-3-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl-methylamino]pyrimidine-5-carboxamide | ||
| Canonical SMILES | CN(CC1=CC2=C(S1)C(=NC(=N2)C3=CN=C(C=C3)OC)N4CCOCC4)C5=NC=C(C=N5)C(=O)NO | ||
| 分子式 | C23H24N8O4S | 分子量 | 508.55 |
| 溶解度 | ≥ 25.45 mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9664 mL | 9.8319 mL | 19.6637 mL |
| 5 mM | 0.3933 mL | 1.9664 mL | 3.9327 mL |
| 10 mM | 0.1966 mL | 0.9832 mL | 1.9664 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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计算结果:
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2.
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CUDC-907 enhances TRAIL-induced apoptosis through upregulation of DR5 in breast cancer cells
CUDC-907 is a novel dual-acting inhibitor of phosphoinositide 3-kinase (PI3K) and histone deacetylase (HDAC). In this study, we aimed to explore the anticancer effects of CUDC-907 on human breast cancer cells. Our results showed that CUDC-907 effectively inhibited breast cancer cell proliferation. Flow cytometry analysis revealed that CUDC-907 induced cell cycle arrest and apoptosis in breast cancer cells. The combined treatment of CUDC-907 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resulted in a marked increase in apoptosis and cleavage of caspase-8, -9 and poly (ADP-ribose) polymerase (PARP) in breast cancer cells. CUDC-907 enhanced expressions of death receptor 5 (DR5), reduced the levels of anti-apoptotic molecules XIAP, Bcl-2 and Bcl-xL. Knockdown of DR5 abrogated apoptosis induced by the combination of CUDC-907 and TRAIL in breast cancer cells. CUDC-907 increased the phosphorylation of JNK and p38 MAPK. JNK inhibitor pretreatment attenuated CUDC-907-induced upregulation of DR5. In summary, CUDC-907 shows potent cytotoxicity against breast cancer cells and facilitates TRAIL-mediated apoptosis through DR5 upregulation. The combination of CUDC-907 and TRAIL may be a promising therapeutic approach in the treatment of breast cancer.
CUDC-907 blocks multiple pro-survival signals and abrogates microenvironment protection in CLL
CUDC-907, a dual PI3K/HDAC inhibitor, has been proposed to have therapeutic potential in hematopoietic malignancies. However, the molecular mechanisms of its effects in chronic lymphocytic leukaemia (CLL) remain elusive. We show that CLL cells are sensitive to CUDC-907, even under conditions similar to the protective microenvironment of proliferation centres. CUDC-907 inhibited PI3K/AKT and HDAC activity, as expected, but also suppressed RAF/MEK/ERK and STAT3 signalling and reduced the expression of anti-apoptotic BCL-2 family proteins BCL-2, BCL-xL, and MCL-1. Moreover, CUDC-907 downregulated cytokines BAFF and APRIL and their receptors BAFFR, TACI, and BCMA, thus blocking BAFF-induced NF-百B signalling. T cell chemokines CCL3/4/17/22 and phosphorylation of CXCR4 were also reduced by CUDC-907. These data indicated that CUDC-907 abrogates different protective signals and suggested that it might sensitize CLL cells to other drugs. Indeed, combinations of low concentrations of CUDC-907 with inhibitors of BCL2, BTK, or the NF-百B pathway showed a potent synergistic effect. Our data indicate that, apart from its known functions, CUDC-907 blocks multiple pro-survival pathways to overcome microenvironment protection in CLL cells. This provides a rationale to evaluate the clinical relevance of CUDC-907 in combination therapies with other targeted inhibitors.
CUDC-907, a dual HDAC and PI3K inhibitor, reverses platinum drug resistance
Platinum (Pt)-based anticancer drugs are the mainstay of treatment for solid cancers. However, resistance to Pt drugs develops rapidly, which can be caused by overexpression of multidrug resistance transporters and activation of DNA repair. CUDC-907 is a potent molecular targeted anticancer agent, rationally designed to simultaneously inhibit histone deacetylase (HDAC) and phosphatidylinositol 3-kinase (PI3K). We investigated the potentiation effect of CUDC-907 on Pt drugs in resistant cancer cells. ABCC2 stably-transfected HEK293 cells and two pairs of parental and Pt-resistant cancer cell lines were used to test for the circumvention of resistance by CUDC-907. Chemosensitivity was assessed by the sulphorhodamine B assay. Drug combinations were evaluated by the median effect analysis. ABCC2 transport activity was examined by flow cytometric assay. Cellular Pt drug accumulation and DNA platination were detected by inductively coupled plasma optical emission spectroscopy. ABCC2, ERCC1 and p21 expression were evaluated by quantitative real-time PCR. Cell cycle analysis and apoptosis assay were performed by standard flow cytometric method. The combination of CUDC-907 with cisplatin were found to exhibit synergistic cytotoxic effect in cisplatin-resistant cancer cells. In Pt-resistant cancer cells, CUDC-907 apparently circumvented the resistance through inhibition of ABCC2 and DNA repair but induction of cell cycle arrest. In the presence of CUDC-907, cellular accumulation of Pt drugs and formation of DNA-Pt adducts were found to be increased whereas expression levels of ABCC2 and ERCC1 was inhibited in Pt-resistant cells. The data advocates further development of CUDC-907 as a resistance reversal agent for use in combination cancer chemotherapy.
CUDC-907, a novel dual PI3K and HDAC inhibitor, in prostate cancer: Antitumour activity and molecular mechanism of action
Targeting the androgen receptor (AR) signalling pathway remains the main therapeutic option for advanced prostate cancer. However, resistance to AR-targeting inhibitors represents a great challenge, highlighting the need for new therapies. Activation of the PI3K/AKT pathway and increased expression of histone deacetylases (HDACs) are common aberrations in prostate cancer, suggesting that inhibition of such targets may be a viable therapeutic strategy for this patient population. Previous reports demonstrated that combination of PI3K inhibitors (PI3KIs) with histone deacetylase inhibitors (HDACIs) resulted in synergistic antitumour activities against preclinical models of prostate cancer. In this study, we demonstrate that the novel dual PI3K and HDAC inhibitor CUDC-907 has promising antitumour activity against prostate cancer cell lines in vitro and castration-resistant LuCaP 35CR patient-derived xenograft (PDX) mouse model in vivo. CUDC-907-induced apoptosis was partially dependent on Mcl-1, Bcl-xL, Bim and c-Myc. Further, down-regulation of Wee1, CHK1, RRM1 and RRM2 contributed to CUDC-907-induced DNA damage and apoptosis. In the LuCaP 35CR PDX model, treatment with CUDC-907 resulted in significant inhibition of tumour growth. These findings support the clinical development of CUDC-907 for the treatment of prostate cancer.
Therapeutic Potential of CUDC-907 (Fimepinostat) for Hepatocarcinoma Treatment Revealed by Tumor Spheroids-Based Drug Screening
Background: Cancer is the second leading cause of death globally. However, most of the new anti-cancer agents screened by traditional drug screening methods fail in the clinic because of lack of efficacy. Choosing an appropriate in vitro tumor model is crucial for preclinical drug screening. In this study, we screened anti-hepatocarcinoma (HCC) drugs using a novel spheroid cell culture device. Methods: Four HCC cell lines were three-dimensionally (3D) cultured to screen 19 small molecular agents. 3D-cultured primary HCC cells and a tumor-bearing mouse model were used to verify the candidate anti-hepatocarcinoma agent. Cell function experiments and western blotting were conducted to explore the anti-hepatocarcinoma mechanism of the candidate agent. Results: We found that CUDC-907 can serve as a potent anti-hepatocarcinoma agent. The study data show that CUDC-907 (fimepinostat), a novel dual acting inhibitor of phosphoinositide 3-kinase (PI3K) and histone deacetylase (HDAC), has potent inhibitory effects on HCC cell lines and primary HCC cells in vitro, Animal studies have shown that CUDC-907 can also suppress HCC cells in vivo. Furthermore, we found that CUDC-907 inhibits the PI3K/AKT/mTOR pathway and downregulates the expression of c-Myc, leading to the suppression of HCC cells. Conclusion: Our results suggest that CUDC-907 can be a candidate anti-HCC drug, and the 3D in vitro drug screening method based on our novel spheroid culture device is promising for future drug screening efforts.