AZD 5153是BET/BRD4溴结构域的双价抑制剂，AZD 5153对BRD4的IC₅₀值为5nM，可同时结合BRD4的两个溴结构域，显著影响MYC、E2F和mTOR的转录程序，并抑制NSD3靶基因的表达。
Cas No.:1869912-39-9
Sample solution is provided at 25 µL, 10mM.
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AZD 5153 is a bivalent BET/BRD4 bromodomain inhibitor with an IC₅₀ of 5nM for BRD4, which simultaneously binds to both bromodomains of BRD4, significantly modulates MYC, E2F, and mTOR transcriptional programs, and inhibits the expression of NSD3 target genes[1-2]. AZD 5153 can be used in research related to hematological malignancies such as acute myeloid leukemia, multiple myeloma, and diffuse large B-cell lymphoma, as well as solid tumors including pancreatic cancer[3-4].
In vitro, AZD 5153 (0.25-2μM) was combined with Gemcitabine (0.5-4μM) to treat human pancreatic cancer cell lines (BXPC-3 and PANC-1) for 12-72 hours. AZD 5153 significantly enhanced the inhibitory effect of Gemcitabine on cell proliferation, synergistically inhibited colony formation, and induced significant apoptosis, characterized by the formation of apoptotic bodies, chromatin condensation, and increased levels of cleaved PARP and cleaved Caspase-3 proteins[5]. AZD 5153 (10-20μM) was combined with the CDK9 inhibitor CDKI-73 (25-100μM) to treat multiple prostate cancer cell lines (LNCaP, V16D, MR49F, PC3) and patient-derived organoid models from castration-resistant prostate cancer (CRPC) for 24 hours. AZD 5153 significantly enhanced the anti-proliferative effects of CDKI-73, leading to a more pronounced reduction in the protein and mRNA levels of pSer2-RNAPII, MCL-1, and MYC[6].
In vivo, AZD 5153 (10mg/kg/day) was administered intraperitoneally to mice bearing H660, LuCaP145.2, or LuCaP35ENZR tumors (five times per week for 21 days, starting when tumor volumes reached approximately 100 mm³). AZD 5153 monotherapy almost completely blocked tumor growth and significantly inhibited the expression of key lineage plasticity program drivers (such as ASCL1 and SOX2) in the tumors[7]. AZD 5153 (3mg/kg) was administered intraperitoneally in combination with the PARP inhibitor olaparib (50mg/kg) to mice bearing ovarian cancer patient-derived xenograft (PDX) or ID8 cells (five times per week from day 14 to day 21 after implantation). AZD 5153 synergized with olaparib to significantly inhibited tumor growth, and by downregulating PTEN expression. AZD 5153 disrupted DNA replication stability, enhanced DNA damage and chromosomal breaks, thereby reversing olaparib resistance[8].
References:
[1] Rhyasen GW, Hattersley MM, Yao Y, et al. AZD5153: A Novel Bivalent BET Bromodomain Inhibitor Highly Active against Hematologic Malignancies. Mol Cancer Ther. 2016 Nov;15(11):2563-2574.
[2] Lin CH, Kuo JC, Li D, et al. AZD5153, a Bivalent BRD4 Inhibitor, Suppresses Hepatocarcinogenesis by Altering BRD4 Chromosomal Landscape and Modulating the Transcriptome of HCC Cells. Front Cell Dev Biol. 2022 Mar 24;10:853652.
[3] Zhang P, Li R, Xiao H, et al. BRD4 Inhibitor AZD5153 Suppresses the Proliferation of Colorectal Cancer Cells and Sensitizes the Anticancer Effect of PARP Inhibitor. Int J Biol Sci. 2019 Jul 21;15(9):1942-1954.
[4] Liu C, Huang Y, Qin T, et al. AZD5153 reverses palbociclib resistance in ovarian cancer by inhibiting cell cycle-related proteins and the MAPK/PI3K-AKT pathway. Cancer Lett. 2022 Mar 1;528:31-44.
[5] Zhu H, Shen M, Zhu Y, et al. AZD5153 enhances the chemo-sensitivity of gemcitabine on pancreatic cancer cells in vitro and in vivo. Cancer Cell Int. 2025 Aug 26;25(1):315.
[6] Rahman R, Rahaman MH, Hanson AR, et al. CDK9 inhibition inhibits multiple oncogenic transcriptional and epigenetic pathways in prostate cancer. Br J Cancer. 2024 Oct;131(6):1092-1105.
[7] Zhang X, Yang Y, Zou H, et al. Effective therapeutic targeting of tumor lineage plasticity in neuroendocrine prostate cancer by BRD4 inhibitors. Acta Pharm Sin B. 2025 Mar;15(3):1415-1429.
[8] Huang Y, Liu C, You L, et al. Synergistic effect of PARP inhibitor and BRD4 inhibitor in multiple models of ovarian cancer. J Cell Mol Med. 2023 Mar;27(5):634-649.
AZD 5153是BET/BRD4溴结构域的双价抑制剂，AZD 5153对BRD4的IC₅₀值为5nM，可同时结合BRD4的两个溴结构域，显著影响MYC、E2F和mTOR的转录程序，并抑制NSD3靶基因的表达[1-2]。AZD 5153可用于急性髓系白血病、多发性骨髓瘤、弥漫性大B细胞淋巴瘤等血液系统恶性肿瘤以及胰腺癌等实体瘤的相关研究[3-4]。
在体外，AZD 5153（0.25-2μM）与Gemcitabine（0.5-4μM）联合处理人胰腺癌细胞系（BXPC-3和PANC-1）12-72小时，AZD 5153显著增强Gemcitabine对细胞增殖的抑制效果，并协同抑制细胞集落形成，联合处理诱导了显著的细胞凋亡，表现为凋亡小体形成、染色质凝集以及Cleaved PARP和Cleaved Caspase-3蛋白水平的升高[5]。AZD 5153（10-20μM）与CDK9抑制剂CDKI-73（25-100μM）联合处理多种前列腺癌细胞系（LNCaP，V16D，MR49F，PC3）和源自去势抵抗性前列腺癌（CRPC）患者类器官模型24小时，AZD 5153显著提高CDKI-73的抗癌细胞增殖作用，并导致pSer2-RNAPII、MCL-1和MYC蛋白及mRNA水平更显著的降低[6]。
在体内，AZD 5153（10mg/kg/day）腹腔注射处理携带H660、LuCaP145.2或LuCaP35ENZR肿瘤的小鼠（从肿瘤体积达到约100mm³开始，每周5次，持续21天），AZD 5153单药治疗能几乎完全阻断肿瘤生长，并显著抑制肿瘤中谱系可塑性程序关键驱动因子（如ASCL1、SOX2）的表达[7]。AZD 5153（3mg/kg）腹腔注射联合PARP抑制剂奥拉帕利（50mg/kg）处理携带卵巢癌患者来源异种移植（PDX）或ID8细胞的小鼠（每周5次，从接种后第14天开始至21天），AZD 5153与奥拉帕利协同显著抑制肿瘤生长，并通过下调PTEN表达破坏DNA复制稳定性，增强DNA损伤和染色体断裂，从而逆转奥拉帕利耐药性[8]。
| Cell experiment [1]: | |
Cell lines | 42D (t-NEPC), H660 (de novo NEPC), LNCaP, V16D, MR49F, PC3 prostate cancer cell lines and patient-derived organoid (PDO) models |
Preparation Method | Cells were maintained in appropriate culture media supplemented with fetal bovine serum at 37°C, 5% CO₂. Cells were treated with AZD 5153 at 0.25-2μM for specified time periods. |
Reaction Conditions | 0.25-2μM; 24-72h |
Applications | AZD 5153 significantly inhibited cell proliferation and colony formation in a dose-dependent manner across all tested prostate cancer cell lines. The inhibitor induced apoptosis, as evidenced by increased cleavage of PARP1 and caspase3. |
| Animal experiment [2]: | |
Animal models | BALB/c nude mice bearing H660, LuCaP145.2, and LuCaP35ENZR prostate cancer xenografts |
Preparation Method | Mice were intraperitoneally administered AZD 5153 (10mg/kg) five times per week for 21 days. Treatment commenced when tumor volumes reached approximately 100mm³. Mice were sacrificed when tumors reached ethical endpoints or at study completion for tumor analysis. |
Dosage form | 10mg/kg; i.p.; Five times per week for 3 weeks. |
Applications | AZD 5153 monotherapy significantly inhibited tumor growth in both de novo neuroendocrine prostate cancer (NEPC) and treatment-induced NEPC patient-derived xenograft (PDX) models, achieving near-complete tumor growth blockade. AZD 5153 also demonstrated superior efficacy compared to JQ1 (50mg/kg) in suppressing tumor growth. Mechanistically, AZD 5153 treatment reduced local chromatin accessibility and H3K27ac marks at lineage plasticity program genes, and decreased expression of key neuroendocrine drivers including ASCL1 and SOX2 in tumor tissues. |
References: | |
| Cas No. | 1869912-39-9 | SDF | |
| 化学名 | (3R)-4-[2-[4-[1-(3-methoxy-1,2,4-triazolo[4,3-b]pyridazin-6-yl)-4-piperidinyl]phenoxy]ethyl]-1,3-dimethyl-2-piperazinone | ||
| Canonical SMILES | COC1=NN=C2N1N=C(N3CCC(C4=CC=C(OCCN5[C@H](C)C(N(C)CC5)=O)C=C4)CC3)C=C2 | ||
| 分子式 | C25H33N7O3 | 分子量 | 479.6 |
| 溶解度 | ≤20mg/ml in ethanol;20mg/ml in DMSO;20mg/ml in dimethyl formamide | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.0851 mL | 10.4254 mL | 20.8507 mL |
| 5 mM | 417 μL | 2.0851 mL | 4.1701 mL |
| 10 mM | 208.5 μL | 1.0425 mL | 2.0851 mL |
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