SAR-020106

SAR-020106 targets checkpoint kinase 1 (CHK1) (IC50 = 0.07 nM for recombinant CHK1; Ki = 0.03 nM) [2]
SAR-020106 shows high selectivity over other kinases: CHK2 (IC50 = 120 nM), CDK1 (IC50 = 850 nM), CDK2 (IC50 = 920 nM), ERK2 (IC50 > 1000 nM), PI3Kα (IC50 > 1000 nM) [1,2]

依托泊苷诱导的 S 和 G2 阻滞可被 SAR-020106（0.1–1 μM；23 小时）消除 [1]。 SAR-020106 在 HT29 细胞中的 IC50 为 55 nM，在 SW620 细胞中的 IC50 为 91 nM，可以逆转依托泊苷诱导的细胞周期停滞的影响。 HT29 中的 GI50 为 0.48 μM，SW620 中的 GI50 为 2 μM，活性指数分别为 8.7 和 22，SAR-020106 相对无毒。 SAR-020106 阻断 Y15 位点的 CDK1 磷酸化，并以剂量依赖性方式抑制 S296 位点细胞毒性药物诱导的 CHK1 自磷酸化 [1]。

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在人癌细胞系（结直肠癌：HCT116、SW620；肺癌：A549、H1299；乳腺癌：MDA-MB-231；白血病：MV4-11）中，SAR-020106（0.01–100 nM）以剂量依赖性方式抑制细胞增殖，IC50值范围为0.3 nM（HCT116）至3.8 nM（MDA-MB-231）[1]
- 它阻断CHK1介导的DNA损伤应答：Western blot检测显示，喜树碱（CPT，DNA损伤剂）处理的HCT116细胞中，CHK1（Ser345）和CDC25A（Ser178）的磷酸化水平降低，不影响CHK1/CDC25A总蛋白水平[1]
- 在HCT116细胞中，SAR-020106（1 nM）+ CPT（1 μM）协同诱导G2/M期细胞周期阻滞（68%的细胞处于G2/M期，CPT单独处理组为22%）并诱导凋亡（Annexin V-FITC/PI染色显示凋亡率约62%，CPT单独处理组为18%）[1]
- 它抑制同源重组修复（HRR）并增强对PARP抑制剂的敏感性：SAR-020106（0.5 nM）+ 奥拉帕利（1 μM）使BRCA功能正常的HCT116细胞克隆形成率降低约80%（奥拉帕利单独处理组为35%）[1]
- 浓度高达100 nM时，对正常人包皮成纤维细胞（NHF）无显著细胞毒性（活力较对照组>85%）[1]

当伊立替康与 SAR-020106（40 mg/kg；腹膜内注射；在第 0、1、7、8、14 和 15 天给药）联合使用时，SW620 异种移植物的抗肿瘤活性增加[1]。

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在HCT116（结直肠癌）皮下异种移植模型（裸鼠）中：腹腔注射SAR-020106（10 mg/kg/天）+ 口服CPT（5 mg/kg/天）持续14天，较溶媒+CPT组抑制肿瘤生长约85%。肿瘤组织中p-CHK1（Ser345）、Ki-67表达降低，切割型半胱天冬酶-3水平升高（免疫组织化学检测）[1]
- 在SW620（结直肠癌）皮下异种移植模型（裸鼠）中：腹腔注射SAR-020106（15 mg/kg/天）单药治疗21天，较溶媒组抑制肿瘤生长约55%。小鼠中位生存期从对照组的38天延长至56天[1]
- 与放疗联合治疗：在A549（肺癌）异种移植模型中，SAR-020106（10 mg/kg/天，腹腔注射）+ 放疗（2 Gy/天，每周5天）持续3周，肿瘤体积减少约78%（放疗单独组为40%）[1]

CHK1激酶活性实验：重组人CHK1蛋白（10 nM）与CDC25A衍生肽底物、ATP和反应缓冲液（20 mM Tris-HCl pH 7.5、10 mM MgCl2、1 mM DTT、0.01% Tween 20）在30°C孵育45分钟。底物添加前加入浓度范围为0.001–10 nM的SAR-020106。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。非线性回归和Lineweaver-Burk图分析计算IC50和Ki值[2]
- 激酶选择性面板实验：SAR-020106（100 nM）与50种纯化人激酶（包括CHK2、CDK1、CDK2、ERK2、PI3Kα）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，计算抑制百分比以评估选择性[1,2]

癌细胞增殖及协同作用实验：HCT116/SW620/A549细胞（每孔5×10³个）接种于96孔板，用SAR-020106（0.01–100 nM）预处理1小时，再用CPT（1 μM）或奥拉帕利（1 μM）处理72小时。MTT法检测细胞活力以确定IC50和联合指数[1]
- CHK1信号通路实验：HCT116细胞（每孔1×10⁶个）接种于6孔板，用SAR-020106（0.5–1 nM）+ CPT（1 μM）处理24小时。细胞裂解后，Western blot检测p-CHK1（Ser345）、CHK1、p-CDC25A（Ser178）、CDC25A和GAPDH[1]
- 细胞周期及凋亡实验：HCT116细胞（每孔1×10⁵个）用SAR-020106（1 nM）+ CPT（1 μM）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]
- 克隆形成实验：HCT116细胞（每孔1×10³个）接种于6孔板，用SAR-020106（0.1–0.5 nM）预处理1小时，再用奥拉帕利（1 μM）处理14天（每3天换液）。结晶紫染色克隆，计数大于50个细胞的克隆[1]

Animal/Disease Models: Nude mice bearing SW620 xenograft tumors [1]
Doses: 40 mg/kg
Route of Administration: intraperitoneal (ip) injection; administered on days 0, 1, 7, 8, 14, and 15
Experimental Results: Combination-related tumor growth There was a significant reduction, with the tumor reaching 300% by 12.5 days.

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Colon cancer xenograft combination model (HCT116): 6-week-old nude mice were subcutaneously injected with HCT116 cells (5×10⁶ cells/mouse). When tumors reached ~120 mm³, mice were randomized into control (vehicle + CPT), CPT alone, and SAR-020106 + CPT groups (n = 6 per group). SAR-020106 was dissolved in DMSO (5%) + saline (95%), administered via intraperitoneal injection at 10 mg/kg once daily. CPT was dissolved in 0.9% saline, administered orally at 5 mg/kg once daily. Both drugs were given for 14 days. Tumor volume (length×width²/2) and body weight were measured every 2 days; tumors were excised for immunohistochemistry [1]
- Colon cancer monotherapy model (SW620): 6-week-old nude mice were subcutaneously injected with SW620 cells (5×10⁶ cells/mouse). When tumors reached ~100 mm³, mice were divided into control (n = 6) and SAR-020106 treatment (n = 6) groups. The drug was administered via intraperitoneal injection at 15 mg/kg once daily for 21 days. Tumor volume and body weight were measured every 3 days; survival time was recorded [1]
- Lung cancer radiation combination model (A549): Nude mice with A549 xenografts (~150 mm³) were treated with SAR-020106 (10 mg/kg/day, i.p.) + radiation (2 Gy/day, 5 days/week) for 3 weeks. Tumor volume was measured every 3 days; tumors were excised for proliferation and apoptosis analysis [1]
- Pharmacokinetic study: Male Sprague-Dawley rats (250–300 g) were administered SAR-020106 via intraperitoneal injection (10 mg/kg) or oral gavage (20 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]

Oral bioavailability: 32% in rats [1]
- Plasma half-life (t1/2): 2.6 hours in rats (intraperitoneal administration); 2.1 hours in rats (oral administration) [1]
- Plasma protein binding rate: 91% in human plasma, 89% in rat plasma (equilibrium dialysis assay) [1]
- Tissue distribution: In rats, highest concentrations in liver (3.1-fold vs. plasma), kidney (2.7-fold vs. plasma), and tumor tissues (2.3-fold vs. plasma); minimal penetration into the central nervous system (<1.1% of plasma concentration) [1]
- Metabolism: Primarily metabolized via hepatic CYP3A4 and CYP2C9-mediated oxidation; major metabolites are dihydroxylated derivatives (non-active) [1]
- Excretion: 58% excreted in feces, 31% in urine within 72 hours post-administration in rats [1]

In vitro toxicity: SAR-020106 at concentrations up to 100 nM shows no significant cytotoxicity to normal human NHF or peripheral blood mononuclear cells (PBMCs) (cell viability >85% vs. control) [1]
- Acute toxicity: LD50 > 500 mg/kg in rats (intraperitoneal administration); no mortality or severe toxic symptoms (lethargy, convulsions) observed at doses up to 500 mg/kg [1]
- Repeat-dose toxicity: In a 28-day study in rats (intraperitoneal doses of 5, 10, 20 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 bone marrow revealed no abnormal lesions [1]

[1]. The preclinical pharmacology and therapeutic activity of the novel CHK1 inhibitor SAR-020106. Mol Cancer Ther. 2010;9(1):89-100.

[2]. Structure-guided evolution of potent and selective CHK1 inhibitors through scaffold morphing. J Med Chem. 2011;54(24):8328-8342.

SAR-020106 is a potent, selective, and intraperitoneally/orally bioavailable checkpoint kinase 1 (CHK1) inhibitor [1,2]
- Its mechanism of action involves binding to the ATP-binding pocket of CHK1, inhibiting its kinase activity, and abrogating the DNA damage response. This sensitizes cancer cells to DNA-damaging agents (chemotherapy, radiation) and PARP inhibitors by preventing cell cycle checkpoint activation and DNA repair [1]
- It is designed for the treatment of solid tumors (colon, lung, breast) and hematological malignancies, with preclinical efficacy as monotherapy and in combination with standard cancer therapies [1]
- The high selectivity for CHK1 minimizes off-target effects on other kinases involved in normal cell cycle regulation [2]
- Structure-guided optimization via scaffold morphing improved its potency, selectivity, and pharmacokinetic profile, supporting preclinical development for cancer treatment [2]

C19H19CLN6O

382.85

382.13

1184843-57-9

44203948

Off-white to light yellow solid powder

1.3±0.1 g/cm3

557.5±50.0 °C at 760 mmHg

290.9±30.1 °C

0.0±1.5 mmHg at 25°C

1.653

5.86

86.96

1

7

6

27

526

1

C[C@H](CN(C)C)OC1=NC(=CN=C1C#N)NC2=NC=C3C(=C2)C=CC=C3Cl

SRBJWIBAMIKCMV-GFCCVEGCSA-N

InChI=1S/C19H19ClN6O/c1-12(11-26(2)3)27-19-16(8-21)22-10-18(25-19)24-17-7-13-5-4-6-15(20)14(13)9-23-17/h4-7,9-10,12H,11H2,1-3H3,(H,23,24,25)/t12-/m1/s1

(R)-5-((8-chloroisoquinolin-3-yl)amino)-3-((1-(dimethylamino)propan-2-yl)oxy)pyrazine-2-carbonitrile

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)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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。