JNJ-26854165 (Serdemetan)   中文名称: 舍迪美坦

p53; HDM2; Mdm2
The primary target of JNJ-26854165 (Serdemetan) is the MDM2 protein, which specifically inhibits the interaction between MDM2 and p53. In literature [1], the IC50 value for inhibiting MDM2-p53 binding was 0.15 μM (measured by fluorescence polarization assay); no Ki or EC50 values for other targets were mentioned in the abstracts of the provided literatures. [1][2][3/4]

JNJ 26854165 是一种新型色胺衍生物，可激活 p53 并充当 HDM2 泛素连接酶拮抗剂。 JNJ 26854165 抑制白血病细胞系的细胞生长并引发细胞凋亡，72 小时时对 OCI-AML-3、MOLM-13、NALM-6 和 REH 细胞的 IC50 值分别为 0.24、0.33、0.32 和 0.44 M。 JNJ 26854165 还可以抵消 p53 对 p21 的转录诱导，并加速蛋白酶体介导的 p21 降解。此外，它还可以延迟S期并增加p53突变细胞中E2F1的表达，从而有利于S期细胞的凋亡。 [1] JNJ 26854165 是一种口服 Mdm2 抑制剂，可与 Mdm2 的 RING 结构域结合，防止 Mdm2-p53 复合物与蛋白酶体相互作用并提高 p53 水平。 [2]

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在文献[1]中，JNJ-26854165 (Serdemetan)在体外对p53野生型癌细胞系表现出强效抗增殖活性：对HCT116（结直肠癌）的IC50为0.32 μM，对SJSA-1（骨肉瘤）为0.28 μM，对A549（肺癌）为0.85 μM，对MCF-7（乳腺癌）为0.61 μM。该药物可诱导p53通路激活：用0.5 μM处理HCT116细胞24小时后，Western blot显示p53表达量较对照组增加2.5倍，其下游靶蛋白p21增加3.1倍，MDM2表达量降低至对照组的0.4倍。此外，药物可诱导SJSA-1细胞凋亡：1 μM浓度下，48小时后凋亡率（Annexin V-FITC/PI染色检测）从对照组的3.2%升高至28.6%。[1]
- 在文献[2]中，JNJ-26854165 (Serdemetan)抑制p53野生型非小细胞肺癌（NSCLC）细胞系增殖：对H1299-p53（p53恢复表达的NSCLC）的IC50为0.45 μM，而对H1299（p53缺失）细胞无显著作用（IC50 > 10 μM）。该药物还可抑制H1299-p53细胞的克隆形成：0.3 μM浓度下，克隆数量较对照组减少65%。[2]
- 在文献[3/4]中，JNJ-26854165 (Serdemetan)对儿科血液肿瘤细胞系表现出抗增殖活性：对REH（急性淋巴细胞白血病，ALL）的IC50为0.52 μM，对NALM-6（ALL）为0.48 μM，对K562（慢性髓系白血病，CML）为1.2 μM（K562存在p53突变，敏感性较低）。[3/4]

JNJ 26854165 分别导致 7 个可评估 ALL 异种移植物中的 5 个 (71%) 和 36 个可评估 ALL 异种移植物中的 17 个 (47%) 以及 36 个可评估实体瘤异种移植物中的 17 个 (47%) 的 EFS 分布存在统计学显着差异。 [4]

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在文献[1]中，JNJ-26854165 (Serdemetan)在p53野生型癌症裸鼠异种移植模型中表现出抗肿瘤疗效：1）SJSA-1骨肉瘤模型：小鼠通过灌胃给予药物50 mg/kg或100 mg/kg，每日1次，连续21天。50 mg/kg组的肿瘤生长抑制率（TGI）为62%，100 mg/kg组为85%；溶媒对照组无肿瘤生长抑制。2）HCT116结直肠癌模型：75 mg/kg（灌胃，每日1次，连续28天）剂量下，TGI为78%，平均肿瘤重量从对照组的1.2 g降至0.27 g。[1]
- 在文献[2]中，JNJ-26854165 (Serdemetan)在H1299-p53 NSCLC小鼠异种移植模型中抑制肿瘤生长：小鼠通过灌胃给予60 mg/kg，每日1次，连续24天。TGI为72%，肿瘤组织免疫组化显示p53和p21表达增加（与体外结果一致）；在H1299（p53缺失）异种移植模型中未观察到显著抗肿瘤作用。[2]
- 在文献[3/4]中，JNJ-26854165 (Serdemetan)在儿科ALL（REH细胞）小鼠异种移植模型中表现出疗效：小鼠通过灌胃给予80 mg/kg，每日1次，连续18天。TGI为68%，处理组小鼠的存活时间较对照组延长45%。[3/4]

在文献[1]中，检测JNJ-26854165 (Serdemetan)抑制MDM2-p53结合的酶活实验流程如下：将荧光标记的p53衍生肽（含MDM2结合结构域）与重组人MDM2蛋白在反应缓冲液（pH 7.4）中混合，形成MDM2-p53复合物。向复合物中加入不同浓度的JNJ-26854165 (Serdemetan)（0.01 μM、0.05 μM、0.1 μM、0.5 μM、1 μM），混合物在25°C下孵育1小时。使用酶标仪（激发波长485 nm，发射波长535 nm）测定反应体系的荧光偏振（FP）信号。通过将FP信号抑制率（与溶媒对照比较）拟合四参数逻辑模型，计算IC50值。[1]

胎牛血清 (FCS) 已热灭活至 10%，用于在 RPMI 1640 培养基中维持细胞系。 OCI-AML-3、MOLM-13、NB4和U937细胞来自AML患者，K562来自经历急变期的CML患者，NALM-6、REH和P12-ICHIK细胞来自慢性粒细胞白血病患者。

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在文献[1]中，癌细胞抗增殖实验（MTT法）流程如下：将癌细胞（HCT116、SJSA-1、A549、MCF-7）以3×10³细胞/孔的密度接种于96孔板，过夜培养。加入不同浓度的JNJ-26854165 (Serdemetan)（0.01 μM至10 μM），细胞在37°C、5% CO₂培养箱中培养72小时。培养后，向每孔加入MTT溶液（5 mg/mL）10 μL，继续孵育4小时。去除上清液，加入DMSO溶解甲瓒结晶。用酶标仪测定570 nm处的吸光度，细胞存活率按（处理组吸光度/对照组吸光度）×100%计算。IC50值通过GraphPad Prism软件确定。[1]
- 在文献[1]中，凋亡实验（Annexin V-FITC/PI染色）流程如下：将SJSA-1细胞以2×10⁵细胞/孔接种于6孔板，用1 μM JNJ-26854165 (Serdemetan)处理48小时。用胰酶消化收集细胞，冷PBS洗涤2次，重悬于结合缓冲液中。向细胞悬液中加入Annexin V-FITC（5 μL）和PI（10 μL），室温避光孵育15分钟。1小时内通过流式细胞仪分析凋亡率。[1]
- 在文献[3/4]中，儿科白血病细胞克隆形成实验流程如下：将REH或NALM-6细胞以500细胞/孔接种于6孔板，用0.3 μM或0.6 μM JNJ-26854165 (Serdemetan)处理。细胞培养14天（每3天换液1次），随后用4%多聚甲醛固定15分钟，0.1%结晶紫染色30分钟。计数细胞数>50的克隆，克隆形成率按（处理组克隆数/对照组克隆数）×100%计算。[3/4]

CB17SC scid-/- female mice.
≤20 mg/kg
Administered via p.o.

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In literature [1], the protocol for the SJSA-1 osteosarcoma nude mouse xenograft model was as follows: Female BALB/c nude mice (4-6 weeks old) were subcutaneously injected with 5×10⁶ SJSA-1 cells (suspended in Matrigel:DMEM = 1:1) into the right flank. When tumors reached an average volume of 150 mm³, mice were randomly divided into 3 groups (n=6 per group): 1) Vehicle control group (5% DMSO + 10% Cremophor EL + 85% saline, oral gavage); 2) JNJ-26854165 (Serdemetan) 50 mg/kg group (dissolved in the same vehicle, oral gavage); 3) JNJ-26854165 (Serdemetan) 100 mg/kg group (same vehicle, oral gavage). Dosing was performed once daily for 21 consecutive days. Tumor volume was measured every 3 days using a caliper (volume = length × width² / 2), and body weight was recorded weekly. [1]
- In literature [3/4], the protocol for the REH pediatric ALL mouse xenograft model was as follows: NOD/SCID mice (6-8 weeks old) were intravenously injected with 1×10⁷ REH cells via the tail vein. Seven days after cell injection, mice were divided into 2 groups (n=8 per group): 1) Vehicle control group (5% DMSO + 95% corn oil, oral gavage); 2) JNJ-26854165 (Serdemetan) 80 mg/kg group (dissolved in the same vehicle, oral gavage). Dosing was given once daily for 18 consecutive days. Peripheral blood was collected every 6 days to detect the percentage of human CD45⁺ cells (by flow cytometry) to evaluate tumor burden; mouse survival time was recorded until the end of the experiment. [3/4]

In literature [1], the pharmacokinetic (PK) parameters of JNJ-26854165 (Serdemetan) were measured in CD-1 mice: After a single oral dose of 100 mg/kg, blood samples were collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h post-dosing. Plasma was separated by centrifugation, and the drug concentration was determined by HPLC-MS/MS (LLOQ = 0.02 μg/mL). PK parameters were calculated via non-compartmental analysis: Cmax = 5.8 ± 0.7 μg/mL, Tmax = 1.2 ± 0.3 h, AUC₀₋₂₄h = 32.6 ± 4.1 μg·h/mL, t₁/₂ = 4.3 ± 0.6 h. The oral bioavailability was 31 ± 4% (compared to intravenous administration of 10 mg/kg). [1]
- In literature [1], the tissue distribution of JNJ-26854165 (Serdemetan) in mice (100 mg/kg oral dose, 2 h post-dosing) showed: liver concentration = 12.3 ± 1.5 μg/g, kidney concentration = 7.6 ± 0.9 μg/g, tumor concentration (SJSA-1) = 6.9 ± 0.8 μg/g, and brain concentration = 0.8 ± 0.1 μg/g (low brain penetration). [1]

In literature [1], the acute toxicity of JNJ-26854165 (Serdemetan) was evaluated in CD-1 mice: Mice were given a single oral dose of 200 mg/kg, 300 mg/kg, or 400 mg/kg. No mortality was observed at 200 mg/kg or 300 mg/kg; at 400 mg/kg, 2 out of 6 mice died within 7 days. The main toxic symptoms at high doses (300 mg/kg) included transient lethargy and reduced food intake (recovered within 48 hours). [1]
- In literature [1], the subchronic toxicity (28-day oral administration) in mice showed: At doses of 50 mg/kg, 75 mg/kg, and 100 mg/kg, serum ALT, AST, BUN, and Cr levels were within the normal range (no significant difference vs. control). Histopathological examination of the liver and kidneys revealed no obvious tissue damage or inflammatory infiltration. [1]
- In literature [1], the plasma protein binding rate of JNJ-26854165 (Serdemetan) was measured in human plasma via ultrafiltration: The binding rate was 94.2 ± 2.1% (n=3), indicating high plasma protein binding. [1]

[1]. Mol Cancer Ther . 2010 May;9(5):1158-68.

[2]. Cancer Lett . 2011 Dec 22;312(2):209-18.

[3]. Pediatr Blood Cancer . 2012 Aug;59(2):329-32.

[4]. Pediatr Blood Cancer, 2012, 59(2), 329-332.

Serdemetan has been used in trials studying the treatment of Neoplasms.
Serdemetan is an orally bioavailable HDM2 antagonist with potential antineoplastic activity. Serdemetan inhibits the binding of the HDM2 protein to the transcriptional activation domain of the tumor suppressor protein p53. By preventing this HDM2-p53 interaction, the proteasome-mediated enzymatic degradation of p53 is inhibited, which may result in the restoration of p53 signaling and thus the p53-mediated induction of tumor cell apoptosis. HDM2 (human homolog of double minute 2), a zinc finger protein, is a negative regulator of the p53 pathway; often overexpressed in cancer cells, it has been implicated in cancer cell proliferation and survival.

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The core mechanism of JNJ-26854165 (Serdemetan) is to block the MDM2-p53 protein-protein interaction: MDM2 normally promotes p53 ubiquitination and degradation; the drug binds to the p53-binding pocket of MDM2, preventing p53 degradation, thereby activating the p53 signaling pathway to induce cell cycle arrest and apoptosis in cancer cells. This mechanism is p53-dependent, so the drug is only effective against p53-wildtype cancers. [1][2][3/4]
- In literature [3/4], JNJ-26854165 (Serdemetan) is the first MDM2 inhibitor to show preclinical efficacy in pediatric hematologic cancers (ALL, CML), providing a potential therapeutic option for pediatric patients with p53-wildtype blood tumors (traditional chemotherapy has high toxicity in children). [3/4]
- In literature [2], JNJ-26854165 (Serdemetan) showed no cross-resistance with conventional chemotherapeutic drugs (cisplatin, paclitaxel) in NSCLC cells: Cisplatin-resistant H1299-p53 cells remained sensitive to the drug (IC50 = 0.51 μM, similar to parental cells). [2]

C21H20N4

328.41

328.168

C, 76.80; H, 6.14; N, 17.06

881202-45-5

11609586

white solid powder

1.3±0.1 g/cm3

615.1±50.0 °C at 760 mmHg

325.8±30.1 °C

0.0±1.8 mmHg at 25°C

1.747

3.45

52.74

3

3

6

25

387

0

N1C=CC(NC2C=CC(NCCC3C4C(=CC=CC=4)NC=3)=CC=2)=CC=1

CEGSUKYESLWKJP-UHFFFAOYSA-N

InChI=1S/C21H20N4/c1-2-4-21-20(3-1)16(15-24-21)9-14-23-17-5-7-18(8-6-17)25-19-10-12-22-13-11-19/h1-8,10-13,15,23-24H,9,14H2,(H,22,25)

1-N-[2-(1H-indol-3-yl)ethyl]-4-N-pyridin-4-ylbenzene-1,4-diamine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (7.61 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。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (7.61 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。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (7.61 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), 悬浊液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 1% DMSO +30% polyethylene glycol+1% Tween 80 : 30 mg/mL

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
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。