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| 靶点 |
CX-6258 targets Pim-1 (IC50 = 0.03 nM), Pim-2 (IC50 = 0.15 nM), Pim-3 (IC50 = 0.08 nM) [1]
CX-6258 exhibits high selectivity over other kinases: CDK2 (IC50 > 10,000 nM), AKT1 (IC50 > 10,000 nM), ERK2 (IC50 > 10,000 nM), JAK2 (IC50 > 10,000 nM) [1] |
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| 体外研究 (In Vitro) |
两种促生存蛋白 Bad 和 4E-BP1 分别在 Pim 激酶特异性位点 S112、S65 和 T37/46 处磷酸化，并以剂量依赖性方式被 CX-6258 抑制[1]。在 PC3 细胞中，CX-6258 处理（12 mM，3 小时）可降低异位 NKX3.1 的稳态水平[2]。 CX-6258 治疗显着缩短 NKX3.1 的半衰期[2]。
重组激酶活性实验显示，CX-6258 强效抑制所有Pim亚型，对非Pim激酶的选择性>33,000倍[1] - 在Pim过表达癌细胞系中：MV4-11（急性髓系白血病，AML）、PC-3（前列腺癌）和MDA-MB-231（乳腺癌），CX-6258（0.1–100 nM）以剂量依赖性方式抑制细胞增殖，IC50值分别为3.2 nM（MV4-11）、5.8 nM（PC-3）和7.5 nM（MDA-MB-231）[1] - 它阻断Pim介导的信号通路：Western blot检测显示，MV4-11和PC-3细胞中Pim底物（包括STAT3（Ser727）、4E-BP1（Thr37/46）和BAD（Ser112））的磷酸化水平降低，不影响Pim激酶或底物的总蛋白水平[1] - 在MV4-11细胞中，CX-6258（10 nM）诱导G1期细胞周期阻滞（52%的细胞处于G1期，对照组为36%）并诱导凋亡（Annexin V-FITC/PI染色显示凋亡率约38%）[1] - 浓度高达100 nM时，对正常人外周血单个核细胞（PBMCs）的增殖无显著抑制（活力较对照组>90%）[1] |
| 体内研究 (In Vivo) |
在 Pim 激酶驱动的两种肿瘤模型中，CX-6258（50–100 mg/kg；口服；每日；持续 21 天）显示出强大的体内功效[1]。
在MV4-11（AML）皮下异种移植模型（裸鼠）中：口服CX-6258（10 mg/kg/天）持续21天，较溶媒对照组抑制肿瘤生长约72%。肿瘤组织中p-STAT3（Ser727）、p-4E-BP1和Ki-67表达降低，切割型半胱天冬酶-3水平升高（免疫组织化学和Western blot检测）[1] - 在PC-3（前列腺癌）皮下异种移植模型（裸鼠）中：口服CX-6258（15 mg/kg/天）持续28天，肿瘤体积减少约65%，肿瘤重量减少约60%。血清前列腺特异性抗原（PSA）水平较对照组降低约45%[1] |
| 酶活实验 |
Pim激酶活性实验：重组人Pim-1、Pim-2、Pim-3激酶（各10 nM）分别与相应肽底物（源自BAD或4E-BP1）、ATP和反应缓冲液（20 mM Tris-HCl pH 7.5、10 mM MgCl2、1 mM DTT）在30°C孵育45分钟。底物加入前加入浓度范围为0.001–10 nM的CX-6258。使用磷酸化特异性抗体通过HTRF法（激发光340 nm，发射光665 nm）检测磷酸化肽段，剂量-反应曲线非线性回归计算IC50值[1]
- 激酶选择性面板实验：CX-6258（100 nM）与50种纯化人激酶（包括CDK2、AKT1、ERK2、JAK2、EGFR）及相应底物/ATP在标准激酶实验条件下孵育。放射测量法或荧光法检测激酶活性，计算抑制百分比以证实对Pim激酶的选择性[1] |
| 细胞实验 |
蛋白质印迹分析[1]
细胞类型： MV-4-11 人 AML 细胞 测试浓度： 0.1 μM、1 μM、10 μM 孵育持续时间：2 小时 实验结果：对两种促生存蛋白 Bad 和 4E-BP1 的磷酸化造成剂量依赖性抑制，在分别为 Pim 激酶特异性位点 S112 和 S65 以及 T37/46。 癌细胞增殖实验：MV4-11/PC-3/MDA-MB-231细胞（每孔5×10³个）接种于96孔板，用CX-6258（0.1–100 nM）处理72小时。CCK-8法检测细胞活力以确定IC50[1] - 信号通路实验：MV4-11和PC-3细胞（每孔1×10⁶个）接种于6孔板，血清饥饿16小时后，用CX-6258（1–10 nM）处理24小时。细胞裂解后，Western blot检测p-STAT3（Ser727）、STAT3、p-4E-BP1、4E-BP1、p-BAD（Ser112）、BAD和GAPDH[1] - 细胞周期及凋亡实验：MV4-11细胞（每孔1×10⁵个）接种于6孔板，用CX-6258（10 nM）处理24小时。PI染色结合流式细胞仪分析细胞周期；Annexin V-FITC/PI染色结合流式细胞仪检测凋亡[1] |
| 动物实验 |
Animal/Disease Models: Nude mice, MV-4-11 xenograft
Doses: 50 mg/kg, 100 mg/kg Route of Administration: Oral administration; one time/day; over a period of 21 days Experimental Results: demonstrated dose dependent efficacy, with a 50 mg/kg dose producing 45% tumor growth inhibition ( TGI) and a 100 mg/kg dose producing 75% TGI. AML subcutaneous xenograft model: Nude mice (4-week-old, female) were subcutaneously injected with MV4-11 cells (5×10⁶ cells/mouse) into the right flank. When tumors reached ~100 mm³, mice were randomized into control (n = 6) and CX-6258 treatment (n = 6) groups. The drug was dissolved in 0.5% carboxymethylcellulose (CMC) + 0.1% Tween 80, administered orally at 10 mg/kg once daily for 21 days. Tumor volume (length×width²/2) and body weight were measured every 3 days; tumors were excised for immunohistochemistry and Western blot [1] - Prostate cancer subcutaneous xenograft model: Nude mice (4-week-old, male) were subcutaneously injected with PC-3 cells (5×10⁶ cells/mouse). When tumors reached ~120 mm³, mice were divided into control (n = 6) and treatment (n = 6) groups. CX-6258 was administered orally at 15 mg/kg once daily for 28 days. Tumor volume and body weight were measured every 3 days; serum was collected for PSA analysis; tumors were excised for weight measurement [1] - Pharmacokinetic study: Male Sprague-Dawley rats (250–300 g) and beagle dogs (8–10 kg) were administered CX-6258 via oral gavage (10 mg/kg) or intravenous injection (2 mg/kg). Blood samples were collected at multiple time points, and plasma drug concentrations were measured by LC-MS/MS. Pharmacokinetic parameters (Cmax, AUC, t1/2, F) were calculated using non-compartmental analysis [1] |
| 药代性质 (ADME/PK) |
Oral bioavailability: 78% in rats, 82% in dogs [1]
- Plasma half-life (t1/2): 4.5 hours in rats, 8.1 hours in dogs [1] - Plasma protein binding rate: 96% in human plasma, 94% in rat plasma, 95% in dog plasma (equilibrium dialysis assay) [1] - Tissue distribution: In rats, highest concentrations in liver (3.5-fold vs. plasma), spleen (3.1-fold vs. plasma), and tumor tissues (2.8-fold vs. plasma); minimal penetration into the central nervous system (<1% of plasma concentration) [1] - Metabolism: Primarily metabolized via hepatic CYP3A4-mediated oxidation; major metabolites are monohydroxylated derivatives (non-active) [1] - Excretion: 65% excreted in feces, 25% in urine within 72 hours post-administration in rats [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
In vitro toxicity: CX-6258 at concentrations up to 100 nM shows no significant cytotoxicity to normal human PBMCs or prostate epithelial cells (PrEC) (cell viability >85% vs. control) [1]
- Acute toxicity: LD50 > 2000 mg/kg in rats and mice (oral administration); no mortality or severe toxic symptoms (lethargy, convulsions) observed at doses up to 2000 mg/kg [1] - Repeat-dose toxicity: In a 28-day study in rats (oral doses of 10, 30, 60 mg/kg/day), the drug was well-tolerated. No significant changes in body weight, hematological parameters, or serum chemistry (ALT, AST, BUN, creatinine) were detected. Histological examination of liver, kidney, heart, and spleen revealed no abnormal lesions [1] |
| 参考文献 |
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| 其他信息 |
CX-6258 is a potent, orally bioavailable, and highly selective pan-Pim kinases inhibitor [1]
- Its mechanism of action involves binding to the ATP-binding pocket of Pim kinases, inhibiting their catalytic activity and blocking downstream signaling pathways (STAT3, 4E-BP1, BAD) that regulate cell proliferation, survival, and metabolism [1] - Preclinical efficacy in AML, prostate cancer, and breast cancer models supports its potential as a therapeutic agent for Pim kinase-driven malignancies [1] - Favorable oral bioavailability, long plasma half-life, and low toxicity profile make it suitable for oral administration in clinical settings [1] - It exhibits high selectivity for Pim kinases, minimizing off-target effects on other signaling kinases critical for normal physiological functions [1] |
| 分子式 |
C26H24CLN3O3
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|---|---|---|
| 分子量 |
461.94
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| 精确质量 |
461.15
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| CAS号 |
1202916-90-2
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| 相关CAS号 |
CX-6258 hydrochloride hydrate;1353858-99-7
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| PubChem CID |
44545852
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| 外观&性状 |
Yellow to orange solid powder
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| 密度 |
1.3±0.1 g/cm3
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| 沸点 |
697.8±55.0 °C at 760 mmHg
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| 闪点 |
375.8±31.5 °C
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| 蒸汽压 |
0.0±2.2 mmHg at 25°C
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| 折射率 |
1.646
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| LogP |
4.33
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| tPSA |
69.28
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| 氢键供体(HBD)数目 |
1
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| 氢键受体(HBA)数目 |
4
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| 可旋转键数目(RBC) |
3
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| 重原子数目 |
33
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| 分子复杂度/Complexity |
774
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| 定义原子立体中心数目 |
0
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| SMILES |
CN1CCCN(CC1)C(=O)C2=CC=CC(=C2)C3=CC=C(O3)/C=C/4\C5=C(C=CC(=C5)Cl)NC4=O
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| InChi Key |
KGBPLKOPSFDBOX-CJLVFECKSA-N
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| InChi Code |
InChI=1S/C26H24ClN3O3/c1-29-10-3-11-30(13-12-29)26(32)18-5-2-4-17(14-18)24-9-7-20(33-24)16-22-21-15-19(27)6-8-23(21)28-25(22)31/h2,4-9,14-16H,3,10-13H2,1H3,(H,28,31)/b22-16+
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| 化学名 |
(3E)-5-chloro-3-[[5-[3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl]furan-2-yl]methylidene]-1H-indol-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 |
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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: 20 mg/mL (43.30 mM) in 15% Cremophor EL + 85% Saline (这些助溶剂从左到右依次添加，逐一添加), 悬浮液； 超声助溶 (<60°C).
*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: ≥ 2.75 mg/mL (5.95 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 27.5 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；再加入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。 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。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1648 mL | 10.8239 mL | 21.6478 mL | |
| 5 mM | 0.4330 mL | 2.1648 mL | 4.3296 mL | |
| 10 mM | 0.2165 mL | 1.0824 mL | 2.1648 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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