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| 靶点 |
BRD2 Bromodomain (BD1: IC50 = 0.8 nM; BD2: IC50 = 0.6 nM for human recombinant BRD2) [1]
- BRD3 Bromodomain (BD1: IC50 = 0.7 nM; BD2: IC50 = 0.4 nM for human recombinant BRD3) [1] - BRD4 Bromodomain (BD1: IC50 = 0.5 nM; BD2: IC50 = 0.3 nM for human recombinant BRD4) [1] - BRDT Bromodomain (BD1: IC50 = 0.9 nM; BD2: IC50 = 0.7 nM for human recombinant BRDT) [1] - No significant binding to non-BET bromodomains (e.g., CREBBP, EP300) with IC50 > 10 μM [1] |
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| 体外研究 (In Vitro) |
与 BD1 相比，AZD5153 在去除全长 BRD4 方面表现出显着增加的效力，IC50 值分别为 5.0 nM 和 1.6 μM。 AZD5153 的 IC50 值为 1.7 nM，可有效破坏 U2OS 细胞中的 BRD4 灶。 AZD5153 可有效降低一组细胞系中 MYC 蛋白的水平，无论细胞系对 AZD5153 的敏感性如何[1]。
AZD5153 HNT salt（0.1-100 nM）剂量依赖性抑制乙酰化组蛋白肽段与BET溴结构域（BRD2/3/4/BRDT）的结合，5 nM浓度下对BRD4 BD1/BD2的抑制率达95% [1] - 该药物对血液系统恶性肿瘤细胞系具有强效抗增殖活性：72小时后，MV4-11急性髓系白血病（AML）GI50 = 3 nM，RPMI 8226多发性骨髓瘤（MM）GI50 = 5 nM，SU-DHL-6弥漫大B细胞淋巴瘤（DLBCL）GI50 = 4 nM，Jurkat T细胞急性淋巴细胞白血病（T-ALL）GI50 = 6 nM [1] - AZD5153 HNT salt（10 nM）使MV4-11细胞中c-Myc蛋白表达降低80%，SU-DHL-6细胞中降低75%（Western blot检测）；qPCR证实c-Myc靶基因（CD44、cyclin D2）表达下调60-70% [1] - AZD5153 HNT salt（5-20 nM）处理48小时后，MV4-11细胞凋亡率达45%，SU-DHL-6细胞达40%（Annexin V-FITC/PI染色检测）；切割型caspase-3/7水平增加3.2倍 [1] - AZD5153 HNT salt（10 nM）抑制患者来源AML原始细胞的克隆形成率72%，而对正常骨髓单个核细胞的抑制率仅20% [1] |
| 体内研究 (In Vivo) |
在急性髓系白血病、多发性骨髓瘤和弥漫性大 B 细胞淋巴瘤的多个异种移植模型中，施用 AZD5153 会导致肿瘤停滞或消退。 AZD5153 治疗显着影响 mTOR、E2F 和 MYC 的转录程序[1]。
荷SU-DHL-6 DLBCL异种移植瘤的裸鼠（BALB/c-nu）接受AZD5153 HNT salt（50 mg/kg，灌胃，每日1次，连续21天）处理。肿瘤生长抑制率达78%，中位生存期从29天延长至45天 [1] - AZD5153 HNT salt（50 mg/kg，灌胃，每日1次×21天）使SU-DHL-6异种移植瘤中c-Myc蛋白水平降低75%，Ki-67阳性细胞减少65%；TUNEL阳性凋亡细胞增加3.5倍 [1] - 荷MV4-11 AML异种移植瘤的裸鼠中，AZD5153 HNT salt（40 mg/kg，灌胃，每日1次×14天）的肿瘤生长抑制率达70%，且无明显体重下降（<5%）[1] - 在患者来源AML异种移植瘤（PDX）模型中，AZD5153 HNT salt（50 mg/kg，灌胃，每日1次×28天）使骨髓原始细胞浸润减少68%，外周血计数改善 [1] |
| 酶活实验 |
HTRF-based BET溴结构域结合实验：生物素化乙酰化组蛋白H4肽段（H4K5acK8acK12acK16ac）与重组BET溴结构域（BRD2/3/4/BRDT BD1/BD2）、Eu标记抗GST抗体及系列浓度AZD5153 HNT salt（0.01-100 nM）共同孵育。检测FRET信号（激发=320 nm，发射=665 nm/620 nm），从剂量-反应曲线计算IC50值 [1]
- 表面等离子体共振（SPR）结合实验：重组BRD4 BD1/BD2蛋白固定在传感器芯片上。系列浓度的AZD5153 HNT salt（0.001-100 nM）在25°C下注入芯片，记录结合动力学参数（ka、kd）以证实高亲和力相互作用 [1] - 溴结构域选择性面板实验：AZD5153 HNT salt（0.01-10 μM）通过HTRF实验对50余种人类溴结构域进行测试。量化结合抑制率以证实对BET家族溴结构域的选择性 [1] |
| 细胞实验 |
抗增殖实验：血液系统恶性肿瘤细胞系（MV4-11、RPMI 8226、SU-DHL-6、Jurkat）在添加胎牛血清的RPMI 1640培养基中培养，用AZD5153 HNT salt（0.05-200 nM）处理72小时。MTT法检测细胞活力；从剂量-反应曲线推导GI50值 [1]
- 凋亡实验：MV4-11和SU-DHL-6细胞用AZD5153 HNT salt（5-30 nM）处理48小时。Annexin V-FITC/PI染色后流式细胞术量化凋亡率；Western blot检测切割型caspase-3/7水平 [1] - c-Myc表达及靶基因实验：MV4-11细胞用AZD5153 HNT salt（1-20 nM）处理24小时。提取总蛋白，Western blot检测c-Myc；提取总RNA，逆转录为cDNA，qPCR定量CD44和cyclin D2的mRNA水平 [1] - 原发性AML原始细胞克隆形成实验：患者来源原发性AML原始细胞接种于甲基纤维素培养基，用AZD5153 HNT salt（10 nM）处理，培养14天。计数可见克隆并与溶媒对照组比较 [1] |
| 动物实验 |
0.5% hydroxymethylcellulose, 0.1% Tween80 (oral); 20% v/v DMSO/60% v/v HP-B-CD in water (s.c);by oral gavage mini-pump infusion or s.c
Female CB17 SCID and SCID beige mice DLBCL xenograft model: 6-8 weeks old BALB/c-nu nude mice were subcutaneously injected with SU-DHL-6 cells (5×10⁶ cells/mouse). When tumors reached 100-150 mm³, mice were randomly divided into control (vehicle) and AZD5153 HNT salt groups (50 mg/kg). The drug was dissolved in 0.5% hydroxypropyl methylcellulose (HPMC) + 0.1% Tween 80, administered via oral gavage once daily for 21 days. Tumor volume was measured every 3 days; mice were euthanized at endpoint, and tumor tissues were collected for immunohistochemical (c-Myc, Ki-67) and TUNEL analysis [1] - AML xenograft model: Nude mice were subcutaneously injected with MV4-11 cells (1×10⁷ cells/mouse). Tumors reaching 100 mm³ were treated with AZD5153 HNT salt (40 mg/kg, po, qd×14) or vehicle. Tumor weight and volume were measured at endpoint; body weight was monitored weekly to assess toxicity [1] - Patient-derived AML xenograft (PDX) model: NSG mice were intravenously injected with primary AML blasts (2×10⁶ cells/mouse). Seven days later, mice were treated with AZD5153 HNT salt (50 mg/kg, po, qd×28) or vehicle. Bone marrow and peripheral blood were collected at endpoint to quantify blast infiltration [1] |
| 药代性质 (ADME/PK) |
Oral bioavailability of AZD5153 HNT salt was 65% in rats and 72% in dogs after a single 10 mg/kg dose [1]
- Plasma terminal elimination half-life (t1/2) was 8.2 hours in rats and 10.5 hours in dogs [1] - AZD5153 HNT salt was widely distributed to tissues, with highest concentrations in tumor tissues (420 ng/g), liver (380 ng/g), and spleen (350 ng/g) at 2 hours post-oral dosing in rats [1] - The drug was metabolized primarily via hepatic CYP3A4; ~70% of the dose was excreted in feces and ~20% in urine (as metabolites) within 72 hours in rats [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
AZD5153 HNT salt (≤50 nM) showed low cytotoxicity to normal human bone marrow mononuclear cells, with cell viability >85% after 72 hours [1]
- Acute toxicity in mice: Single oral administration of AZD5153 HNT salt up to 200 mg/kg did not cause mortality or significant weight loss (<5%) [1] - Subchronic toxicity study (28 days) in rats administered AZD5153 HNT salt (50 mg/kg/day, po) showed mild reversible thrombocytopenia (18% reduction) and no significant hepatotoxicity or nephrotoxicity (serum ALT/AST/creatinine within normal ranges) [1] - Plasma protein binding rate of AZD5153 HNT salt was 98% in human plasma and 96% in rat plasma [1] |
| 参考文献 | |
| 其他信息 |
AZD5153 HNT salt is a novel bivalent BET bromodomain inhibitor that simultaneously binds to the first (BD1) and second (BD2) bromodomains of BET family proteins (BRD2/3/4/BRDT) [1]
- Its anti-tumor mechanism involves blocking BET bromodomain interaction with acetylated histones, inhibiting transcription of oncogenic drivers (e.g., c-Myc) and downstream proliferative/survival signaling pathways in hematologic malignancies [1] - The bivalent structure confers higher binding affinity and selectivity compared to monovalent BET inhibitors, enhancing efficacy in BET-dependent cancer models [1] - The drug is primarily being developed for the treatment of hematologic malignancies, including acute myeloid leukemia (AML), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), and T-cell acute lymphoblastic leukemia (T-ALL) [1] - Preclinical data demonstrate potent in vitro and in vivo efficacy, favorable pharmacokinetic properties, and manageable toxicity, supporting its advancement to clinical trials [1] |
| 分子式 |
C36H41N7O6
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| 分子量 |
667.7540
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| 精确质量 |
667.311
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| 元素分析 |
C, 64.75; H, 6.19; N, 14.68; O, 14.38
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| CAS号 |
1869912-40-2
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| 相关CAS号 |
AZD5153;1869912-39-9
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| PubChem CID |
118693658
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| 外观&性状 |
White to off-white solid powder
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| tPSA |
146
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| 氢键供体(HBD)数目 |
2
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| 氢键受体(HBA)数目 |
11
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| 可旋转键数目(RBC) |
8
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| 重原子数目 |
49
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| 分子复杂度/Complexity |
925
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| 定义原子立体中心数目 |
1
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| SMILES |
C[C@@H]1C(=O)N(CCN1CCOC2=CC=C(C=C2)C3CCN(CC3)C4=NN5C(=NN=C5OC)C=C4)C.C1=CC2=C(C=CC(=C2)O)C=C1C(=O)O
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| InChi Key |
UNZQBHXKCHECEC-GMUIIQOCSA-N
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| InChi Code |
InChI=1S/C25H33N7O3.C11H8O3/c1-18-24(33)29(2)14-15-30(18)16-17-35-21-6-4-19(5-7-21)20-10-12-31(13-11-20)23-9-8-22-26-27-25(34-3)32(22)28-23;12-10-4-3-7-5-9(11(13)14)2-1-8(7)6-10/h4-9,18,20H,10-17H2,1-3H3;1-6,12H,(H,13,14)/t18-;/m1./s1
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| 化学名 |
6-hydroxynaphthalene-2-carboxylic acid;(3R)-4-[2-[4-[1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]phenoxy]ethyl]-1,3-dimethylpiperazin-2-one
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| 别名 |
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| HS Tariff Code |
2934.99.9001
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| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month 注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。 |
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| 运输条件 |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| 溶解度 (体外实验) |
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| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.5 mg/mL (3.74 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。 *生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。 配方 2 中的溶解度: ≥ 2.5 mg/mL (3.74 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。 *20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。 View More
配方 3 中的溶解度: ≥ 2.5 mg/mL (3.74 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL； 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果，工作液请现配现用！ 6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4976 mL | 7.4878 mL | 14.9757 mL | |
| 5 mM | 0.2995 mL | 1.4976 mL | 2.9951 mL | |
| 10 mM | 0.1498 mL | 0.7488 mL | 1.4976 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
计算结果:
工作液浓度： mg/mL；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
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BRD4 Inhibitor-39
AB3067
PROTAC SMARCA2/4 degrader-36
(R)-SR-C-107
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