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| 靶点 |
BAY 1238097 demonstrated potent inhibitory action (IC50 < 100 nM) in a TR-FRET test employing an acetylated peptide sourced from histone H4 and BET BRD4 bromodomain 1. The interaction between H4 (IC50=2430 nM), BRD4 (IC50=63 nM), and BRD3 or BRD2 (IC50=609 nM) is suppressed in the NanoBRET experiment [1]. In lymphoma models, BAY 1238097 demonstrates anticancer efficacy in vitro. GCB DLBCL cells' gene expression is impacted by BAY 1238097. The most downregulated genes at the gene level were BTK, CCDC86, CCND2, CD19, CD27, FAIM, FCMR (FAIM3), IL7R, IRAK1, MAPK13, MYB, MYC, PDE4B, TNFRSF13B, and TNFRSF17. Genes that are up-regulated in addition to those that code for histones include CCL5, CDKN2C, CD69, JUN, and MKNK2 [2].
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| 体外研究 (In Vitro) |
BAY 1238097 在使用源自组蛋白 H4 和 BET BRD4 溴结构域 1 的乙酰化肽的 TR-FRET 测试中表现出有效的抑制作用 (IC50 < 100 nM)。H4 (IC50=2430 nM)、BRD4 (IC50=63 nM) 之间的相互作用，并且 BRD3 或 BRD2 (IC50=609 nM) 在 NanoBRET 实验中被抑制 [1]。在淋巴瘤模型中，BAY 1238097 表现出体外抗癌功效。 GCB DLBCL 细胞的基因表达受到 BAY 1238097 的影响。基因水平上下调最多的基因是 BTK、CCDC86、CCND2、CD19、CD27、FAIM、FCMR (FAIM3)、IL7R、IRAK1、MAPK13、MYB、MYC、PDE4B、 TNFRSF13B 和 TNFRSF17。除了编码组蛋白的基因外，上调的基因还包括 CCL5、CDKN2C、CD69、JUN 和 MKNK2 [2]。
BAY 1238097 在包含51个淋巴瘤来源的细胞系组中显示出抗增殖活性，其中位半数抑制浓度（IC50）为231 nmol/L（95%置信区间：161-280 nmol/L）。其在B细胞淋巴瘤模型中的活性高于T细胞淋巴瘤模型。[2] BAY 1238097 的抗肿瘤活性主要是细胞抑制性的。处理（500 nmol/L，72小时）可在数个弥漫性大B细胞淋巴瘤（DLBCL）细胞系中诱导细胞周期停滞在G1期，并减少G2/M期细胞。[2] 在用500 nmol/L BAY 1238097 处理72或96小时的八个细胞系中观察到时间依赖性的细胞凋亡。[2] 对生发中心B细胞（GCB）DLBCL细胞系（DOHH-2）暴露于500 nmol/L BAY 1238097 8、12或24小时的基因表达谱（GEP）分析显示，MYC、NOTCH、E2F的靶基因以及NF-κB/MYD88和mTOR/AKT信号通路成员被下调。上调的转录本主要代表组蛋白。[2] BAY 1238097 在体外与EZH2抑制剂DZNep和GSK126具有协同作用，尤其是在EZH2突变的GCB-DLBCL细胞系中。[2] BAY 1238097 在体外与mTOR抑制剂依维莫司在测试的8个DLBCL细胞系中的7个具有协同作用。[2] BAY 1238097 在体外与BTK抑制剂伊布替尼在2个携带MYD88 L265P突变的ABC-DLBCL细胞系中具有协同作用，但在MYD88野生型的ABC-DLBCL细胞中未观察到益处。[2] BAY 1238097 处理下调了GCB-DLBCL细胞系中的EZH2蛋白水平和组蛋白修饰H3K27me3（EZH2活性的标志物）。与GSK126联用导致H3K27me3更显著的下调。[2] BAY 1238097（500 nmol/L）处理下调了两个GCB-DLBCL细胞系中的磷酸化AKT（pAKT）水平。[2] 在DLBCL细胞系中进行的染色质免疫沉淀（ChIP）实验显示，用500 nmol/L BAY 1238097 处理3小时减少了BRD4与EZH2基因上游调控区域的结合。[2] EZH2基因体细胞突变的存在与GCB-DLBCL细胞系对BAY 1238097的更高敏感性相关。MYD88 L265P突变与ABC-DLBCL细胞系的更高敏感性相关。[2] |
| 体内研究 (In Vivo) |
BAY 1238097 在 AML 和 MM 模型中证明了强大的有效性。在淋巴瘤模型中，BAY 1238097 表现出体内抗癌功效 [1][2]。在几种疾病模型中，每天以 10-15 mg/kg 的剂量施用 BAY 1238097，持续 9-14 天，耐受性良好，并且没有显示出毒性迹象 [1][2]。
在SU-DHL-8（GCB-DLBCL）异种移植模型（建立于SCID小鼠中）中，口服给予BAY 1238097，按其最大耐受剂量（MTD）15 mg/kg每日一次，连续12天，与载体对照组相比，显著抑制了肿瘤生长。在接种后第14天，治疗组/对照组（T/C）肿瘤体积比率为15%。[2] 在OCI-LY-3（ABC-DLBCL）异种移植模型（建立于SCID小鼠中）中，口服给予BAY 1238097，按其MTD 45 mg/kg每周两次，连续4周，显著抑制了肿瘤生长。在接种后第48天，T/C比率为23%。[2] |
| 细胞实验 |
使用标准MTT（3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐）法评估BAY 1238097的抗增殖活性。将淋巴瘤细胞系暴露于不同浓度的化合物中72小时。测量吸光度，并根据剂量反应曲线计算IC50和LC50值。[2]
通过用膜联蛋白V和7-氨基放线菌素D（7-AAD）对BAY 1238097处理后的细胞进行染色来评估细胞凋亡。通过流式细胞术分析细胞以量化凋亡细胞百分比。[2] 通过流式细胞术分析BAY 1238097处理后的细胞周期分布。固定细胞、透化，用DNA结合染料（如碘化丙啶）染色，测量DNA含量以确定处于细胞周期不同阶段（G1期、S期、G2/M期）的细胞百分比。[2] 对于蛋白质印迹（Western blotting），裂解细胞并提取蛋白质。通过SDS-PAGE分离蛋白质，转移至膜上，并用特异性一抗（如抗BRD4、MYC、EZH2、H3K27me3、组蛋白H3、磷酸化AKT、AKT、磷酸化mTOR、GAPDH的抗体）进行孵育。与偶联辣根过氧化物酶的适当二抗孵育后，使用化学发光法检测信号。[2] 进行染色质免疫沉淀（ChIP）以评估BRD4与EZH2启动子区域的结合。用BAY 1238097或DMSO处理细胞，用甲醛交联并裂解。超声处理染色质以剪切DNA。使用特异性抗BRD4抗体免疫沉淀BRD4结合的DNA片段。逆转交联后，使用针对EZH2上游调控区域的特异性引物，通过定量实时PCR对纯化的DNA进行定量。[2] 使用微阵列技术（HumanHT-12 v4表达珠芯片）进行基因表达谱分析。从用BAY 1238097或DMSO对照处理的细胞中提取总RNA，标记并杂交到微阵列芯片上。扫描荧光信号，并分析数据以识别差异表达基因。进行基因集富集分析（GSEA）以识别富集的生物学通路。[2] 通过将细胞暴露于BAY 1238097和第二种药物（如GSK126、依维莫司、伊布替尼）的单独及联合系列稀释液中进行药物联合研究。72小时后测量细胞活力。使用Chou-Talalay方法计算联合指数（CI）来确定协同、相加或拮抗作用。CI < 0.9表示协同作用，CI在0.9至1.1之间表示相加作用，CI > 1.1表示无益/拮抗作用。[2] |
| 动物实验 |
Animal/Disease Models: Severe combined immunodeficiency (SCID) female mice (9-12 weeks old) were inoculated subcutaneously (sc) (sc) in the right flank with 5×106 SU-DHL-8 cells/mouse, suspended in 0.1 mL Matrigel or treated with O.
Doses: 15 mg/kg (maximum tolerated dose). Route of Administration: Take orally daily for 12 days (day 21 after tumor inoculation). Experimental Results: demonstrated strong efficacy in AML models THP-1, MOLM-13 and KG-1 with T/C between 13% and 20%. It is also active in the MM model of the human IGH-cyclin D1 translocation MOLP-8 model with a T/C of 3% [2]. For in vivo efficacy studies, severe combined immunodeficiency (SCID) female mice (9-12 weeks old) were used. In the SU-DHL-8 (GCB-DLBCL) model, mice were inoculated subcutaneously with 5 × 10^6 SU-DHL-8 cells suspended in Matrigel. Treatment began on day 4 post-inoculation. BAY 1238097 was formulated as a solution in 0.9% NaCl in water, adjusted to pH 4. It was administered orally (p.o.) at a dose volume of 10 ml/kg. The treatment group received BAY 1238097 at its maximum tolerated dose (MTD) of 15 mg/kg once daily for 12 consecutive days. The control group received the vehicle solution. Tumor volumes were measured twice a week. [2] In the OCI-LY-3 (ABC-DLBCL) model, mice were inoculated subcutaneously with OCI-LY-3 tumor fragments. Treatment started on day 21 post-inoculation when tumors reached a median size. BAY 1238097 was formulated as above and administered orally (p.o.) at its MTD of 45 mg/kg using an intermittent schedule (twice a week) for 4 weeks. The control group received the vehicle solution. Tumor volumes were measured twice a week. [2] Body weight was monitored daily as an indicator of toxicity. [2] |
| 毒性/毒理 (Toxicokinetics/TK) |
The maximum tolerated dose (MTD) of BAY 1238097 was determined to be 15 mg/kg for daily administration and 45 mg/kg for twice-weekly administration in SCID mice bearing lymphoma xenografts. [2]
In the SU-DHL-8 model, treatment with 15 mg/kg daily resulted in a maximal mean body weight loss of 6%. In the OCI-LY-3 model, treatment with 45 mg/kg twice weekly resulted in a maximal mean body weight loss of 9%. Body weight loss ≥20% was predefined as excessive toxicity, which was not observed at the MTDs used. [2] |
| 参考文献 | |
| 其他信息 |
BET Inhibitor BAY1238097 is an inhibitor of the Bromodomain (BRD) and Extra-Terminal domain (BET) family of proteins, with potential antineoplastic activity. Upon administration, the BET inhibitor BAY1238097 binds to the acetylated lysine recognition motifs on the BRD of BET proteins, thereby preventing the interaction between BET proteins and histones. This disrupts chromatin remodeling and prevents the expression of certain growth-promoting genes. This leads to an inhibition of tumor cell growth. BET proteins (BRD2, BRD3, BRD4 and BRDT) are transcriptional regulators that bind to acetylated lysines on the tails of histones H3 and H4, and regulate chromatin structure and function; they play an important role in the modulation of gene expression during development and cellular growth.
BAY 1238097 is a novel BET bromodomain inhibitor with promising preclinical anti-lymphoma activity. [2] Its mechanism of action involves interference with the transcription of key oncogenes and signaling pathways (e.g., MYC, NF-κB, mTOR) by inhibiting the binding of BET proteins (like BRD4) to acetylated histones. [2] Sensitivity to BAY 1238097 was associated with specific genetic features, such as EZH2 mutations in GCB-DLBCL and MYD88 L265P mutations in ABC-DLBCL, suggesting potential predictive biomarkers. [2] The study proposes rational combination strategies for BAY 1238097 with inhibitors of EZH2, mTOR, and BTK based on observed in vitro synergism and shared pathway disruptions. [2] |
| 分子式 |
C25H33N5O3
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|---|---|
| 分子量 |
451.561225652695
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| 精确质量 |
451.258
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| CAS号 |
1564268-08-1
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| 相关CAS号 |
(R)-BAY1238097;1564269-85-7
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| PubChem CID |
118237331
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| 外观&性状 |
Light yellow to yellow solid powder
|
| LogP |
2.4
|
| tPSA |
69.6
|
| 氢键供体(HBD)数目 |
1
|
| 氢键受体(HBA)数目 |
6
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| 可旋转键数目(RBC) |
4
|
| 重原子数目 |
33
|
| 分子复杂度/Complexity |
688
|
| 定义原子立体中心数目 |
1
|
| SMILES |
C1(C2=CC=C(N3CCN(C)CC3)C=C2)C2=CC(OC)=C(OC)C=C2C[C@H](C)N(C(NC)=O)N=1
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| InChi Key |
CJIPEACKIJJYED-KRWDZBQOSA-N
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| InChi Code |
InChI=1S/C25H33N5O3/c1-17-14-19-15-22(32-4)23(33-5)16-21(19)24(27-30(17)25(31)26-2)18-6-8-20(9-7-18)29-12-10-28(3)11-13-29/h6-9,15-17H,10-14H2,1-5H3,(H,26,31)/t17-/m0/s1
|
| 化学名 |
(S)-7,8-dimethoxy-N,4-dimethyl-1-(4-(4-methylpiperazin-1-yl)phenyl)-4,5-dihydro-3H-benzo[d][1,2]diazepine-3-carboxamide
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| 别名 |
S-isomer of BAY-1238097; BAY1238097; BAY-1238097; BAY 1238097; BAY 12-38097; BAY 123; BAY-123; BAY12-38097; BAY-12-38097
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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（例如氮气保护），避免吸湿/受潮。 |
| 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) |
DMSO : ~150 mg/mL (~332.18 mM)
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|---|---|
| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.5 mg/mL (5.54 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 (5.54 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 (5.54 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 | 2.2145 mL | 11.0727 mL | 22.1455 mL | |
| 5 mM | 0.4429 mL | 2.2145 mL | 4.4291 mL | |
| 10 mM | 0.2215 mL | 1.1073 mL | 2.2145 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) 。
The BET inhibitor BAY 1238097 has anti‐proliferative activityinvitroandinvivoin models of B‐cell lymphomas. |
BAY 1238097 hasinvivoanti‐proliferative activity in models of diffuse large B‐cell lymphoma.Br J Haematol. 2017 Sep;178(6):936-948. |
BAY 1238097 affects the gene expression of GCB DLBCL cells.Br J Haematol. 2017 Sep;178(6):936-948. |
BAY 1238097 showsinvitrosynergism with the mTOR inhibitor everolimus. |
BAY 1238097 showsinvitrosynergism with EZH2 inhibitors with a decrease in EZH2 protein levels and H3K27me3.Br J Haematol. 2017 Sep;178(6):936-948. |
EZH2mutational status is associated with sensitivity to BAY 1238097 and both JQ1 and BAY 1238097 decrease BRD4 binding to EZH2 promoter region.Br J Haematol. 2017 Sep;178(6):936-948. |
BRD4 Inhibitor-39
AB3067
PROTAC SMARCA2/4 degrader-36
(R)-SR-C-107
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