SAR-020106
目录号 : GC61266
SAR-020106 is an ATP-competitive, potent, and selective CHK1 inhibitor with an IC50 of 13.3 nM.
Cas No.:1184843-57-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
SAR-020106 is an ATP-competitive, potent, and selective CHK1 inhibitor with an IC50 of 13.3 nM.
SAR-020106 abrogates an etoposide-induced G2 arrest with an IC50 of 55 nmol/L in HT29 cells, and significantly enhances the cell killing of gemcitabine and SN38 by 3.0- to 29-fold in several colon tumor lines in vitro and in a p53-dependent fashion. SAR-020106 inhibits cytotoxic drug-induced autophosphorylation of CHK1 at S296 and blocks the phosphorylation of CDK1 at Y15 in a dose-dependent fashion[1].
SAR-020106 can enhance the antitumor effects of both irinotecan and gemcitabine in vivo with appropriate biomarker changes and minimal toxicity[1]. Although having minimal oral bioavailability in mice (F = 5%), distribution of SAR-020106 following i.p. dosing (40 mg/kg) was sufficient to inhibit CHK1 in the tumors, as shown by inhibition of the irinotecan-induced CHK1 pS296 autophosphorylation. At doses giving inhibition of CHK1 activity in vivo, the selective CHK1 inhibitor SAR-020106 showed no single agent activity in the SW620 xenograft model, and tumors grew at similar rates to the vehicle-treated controls. When dosed (i.p.) in combination with irinotecan, SAR-020106 was observed to potentiate the antitumor activity of the genotoxic drug in the SW620 xenograft model[2].
[1] Walton MI, et al. Mol Cancer Ther. 2010, 9(1):89-100. [2] Reader JC, et al. J Med Chem. 2011, 54(24):8328-42.
| Cas No. | 1184843-57-9 | SDF | |
| Canonical SMILES | N#CC1=NC=C(NC2=CC3=C(C=N2)C(Cl)=CC=C3)N=C1O[C@H](C)CN(C)C | ||
| 分子式 | C19H19ClN6O | 分子量 | 382.85 |
| 溶解度 | DMSO: 5 mg/mL (13.06 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.612 mL | 13.0599 mL | 26.1199 mL |
| 5 mM | 0.5224 mL | 2.612 mL | 5.224 mL |
| 10 mM | 0.2612 mL | 1.306 mL | 2.612 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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，
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 saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
The Chk1 inhibitor SAR-020106 sensitizes human glioblastoma cells to irradiation, to temozolomide, and to decitabine treatment
J Exp Clin Cancer Res 2019 Oct 21;38(1):420.PMID:31639020DOI:10.1186/s13046-019-1434-2.
Background: Glioblastoma is the most common and aggressive brain tumour in adults with a median overall survival of only 14 months after standard therapy with radiation therapy (IR) and temozolomide (TMZ). In a novel multimodal treatment approach we combined the checkpoint kinase 1 (Chk1) inhibitor SAR-020106 (SAR), disrupting homologue recombination, with standard DNA damage inducers (IR, TMZ) and the epigenetic/cytotoxic drug decitabine (5-aza-2'-deoxycitidine, 5-aza-dC). Different in vitro glioblastoma models are monitored to evaluate if the impaired DNA damage repair may chemo/radiosensitize the tumour cells. Methods: Human p53-mutated (p53-mut) and -wildtype (p53-wt) glioblastoma cell lines (p53-mut: LN405, T98G; p53-wt: A172, DBTRG) and primary glioblastoma cells (p53-mut: P0297; p53-wt: P0306) were treated with SAR combined with TMZ, 5-aza-dC, and/or IR and analysed for induction of apoptosis (AnnexinV and sub-G1 assay), cell cycle distribution (nuclear PI staining), DNA damage (alkaline comet or gH2A.X assay), proliferation inhibition (BrdU assay), reproductive survival (clonogenic assay), and potential tumour stem cells (nestinpos/GFAPneg fluorescence staining). Potential treatment-induced neurotoxicity was evaluated on nestin-positive neural progenitor cells in a murine entorhinal-hippocampal slice culture model. Results: SAR showed radiosensitizing effects on the induction of apoptosis and on the reduction of long-term survival in p53-mut and p53-wt glioblastoma cell lines and primary cells. In p53-mut cells, this effect was accompanied by an abrogation of the IR-induced G2/M arrest and an enhancement of IR-induced DNA damage by SAR treatment. Also TMZ and 5-aza-dC acted radioadditively albeit to a lesser extent. The multimodal treatment achieved the most effective reduction of clonogenicity in all tested cell lines and did not affect the ratio of nestinpos/GFAPneg cells. No neurotoxic effects were detected when the number of nestin-positive neural progenitor cells remained unchanged after multimodal treatment. Conclusion: The Chk1 inhibitor SAR-020106 is a potent sensitizer for DNA damage-induced cell death in glioblastoma therapy strongly reducing clonogenicity of tumour cells. Selectively enhanced p53-mut cell death may provide stronger responses in tumours defective of non-homologous end joining (NHEJ). Our results suggest that a multimodal therapy involving DNA damage inducers and DNA repair inhibitors might be an effective anti-tumour strategy with a low risk of neurotoxicity.
Targeted radiosensitization by the Chk1 inhibitor SAR-020106
Int J Radiat Oncol Biol Phys 2013 Mar 15;85(4):1110-8.PMID:22981708DOI:10.1016/j.ijrobp.2012.08.006.
Purpose: To explore the activity of a potent Chk1 inhibitor (SAR-020106) in combination with radiation. Methods and materials: Colony and mechanistic in vitro assays and a xenograft in vivo model. Results: SAR-020106 suppressed-radiation-induced G2/M arrest and reduced clonogenic survival only in p53-deficient tumor cells. SAR-020106 promoted mitotic entry following irradiation in all cell lines, but p53-deficient cells were likely to undergo apoptosis or become aneuploid, while p53 wild-type cells underwent a postmitotic G1 arrest followed by subsequent normal cell cycle re-entry. Following combined treatment with SAR-020106 and radiation, homologous-recombination-mediated DNA damage repair was inhibited in all cell lines. A significant increase in the number of pan-γH2AX-staining apoptotic cells was observed only in p53-deficient cell lines. Efficacy was confirmed in vivo in a clinically relevant human head-and-neck cell carcinoma xenograft model. Conclusion: The Chk1 inhibitor SAR-020106 is a potent radiosensitizer in tumor cell lines defective in p53 signaling.
CXCL2-mediated ATR/CHK1 signaling pathway and platinum resistance in epithelial ovarian cancer
J Ovarian Res 2021 Sep 3;14(1):115.PMID:34474677DOI:10.1186/s13048-021-00864-3.
Tumor microenvironment and chemokines play a significant role in cancer chemoresistance. This study was designed to reveal the important role of CXCL2 in platinum resistance in epithelial ovarian cancer (EOC). Differently expressed (DE) genes were screen out based on analysis of GSE114206 dataset in GEO database. The expression of DE chemokines was further validated in platinum- resistant and sensitive EOC. Cell viability assay and cell apoptosis assay were performed to explore the roles of CXCL2 in EOC. Cell stemness characteristics and the signaling pathway regulated by CXCL2 were also investigated in this study. As the results showed, CXCL2 was identified up-regulated in platinum-resistant EOC. The functional assays showed overexpressing CXCL2 or co-culturing with recombinant human CXCL2 promoted cell resistance to cisplatin. Conversely, knocking down CXCL2 or co-culturing with neutralizing antibody to CXCL2 increased cell response to cisplatin. CXCL2 overexpressing maintained cell stemness and activated ATR/CHK1 signaling pathway in EOC. Moreover, we further demonstrated that CXCL2-mediated resistance to cisplatin could be saved by SB225002, the inhibitor of CXCL2 receptor, as well as be rescued by SAR-020106, the inhibitor of ATR/CHK1 signaling pathway. This study identified a CXCL2-mediated mechanism in EOC platinum resistance. Our findings provided a novel target for chemoresistance prevention in EOC.
The preclinical pharmacology and therapeutic activity of the novel CHK1 inhibitor SAR-020106
Mol Cancer Ther 2010 Jan;9(1):89-100.PMID:20053762DOI:10.1158/1535-7163.MCT-09-0938.
Genotoxic antitumor agents continue to be the mainstay of current cancer chemotherapy. These drugs cause DNA damage and activate numerous cell cycle checkpoints facilitating DNA repair and the maintenance of genomic integrity. Most human tumors lack functional p53 and consequently have compromised G(1)-S checkpoint control. This has led to the hypothesis that S and G(2)-M checkpoint abrogation may selectively enhance genotoxic cell killing in a p53-deficient background, as normal cells would be rescued at the G(1)-S checkpoint. CHK1 is a serine/threonine kinase associated with DNA damage-linked S and G(2)-M checkpoint control. SAR-020106 is an ATP-competitive, potent, and selective CHK1 inhibitor with an IC(50) of 13.3 nmol/L on the isolated human enzyme. This compound abrogates an etoposide-induced G(2) arrest with an IC(50) of 55 nmol/L in HT29 cells, and significantly enhances the cell killing of gemcitabine and SN38 by 3.0- to 29-fold in several colon tumor lines in vitro and in a p53-dependent fashion. Biomarker studies have shown that SAR-020106 inhibits cytotoxic drug-induced autophosphorylation of CHK1 at S296 and blocks the phosphorylation of CDK1 at Y15 in a dose-dependent fashion both in vitro and in vivo. Cytotoxic drug combinations were associated with increased gammaH2AX and poly ADP ribose polymerase cleavage consistent with the SAR-020106-enhanced DNA damage and tumor cell death. Irinotecan and gemcitabine antitumor activity was enhanced by SAR-020106 in vivo with minimal toxicity. SAR-020106 represents a novel class of CHK1 inhibitors that can enhance antitumor activity with selected anticancer drugs in vivo and may therefore have clinical utility.
Optimising measles virus-guided radiovirotherapy with external beam radiotherapy and specific checkpoint kinase 1 inhibition
Radiother Oncol 2013 Jul;108(1):24-31.PMID:23849174DOI:10.1016/j.radonc.2013.05.036.
Background and purpose: We previously reported a therapeutic strategy comprising replication-defective NIS-expressing adenovirus combined with radioiodide, external beam radiotherapy (EBRT) and DNA repair inhibition. We have now evaluated NIS-expressing oncolytic measles virus (MV-NIS) combined with NIS-guided radioiodide, EBRT and specific checkpoint kinase 1 (Chk1) inhibition in head and neck and colorectal models. Materials and methods: Anti-proliferative/cytotoxic effects of individual agents and their combinations were measured by MTS, clonogenic and Western analysis. Viral gene expression was measured by radioisotope uptake and replication by one-step growth curves. Potential synergistic interactions were tested in vitro by Bliss independence analysis and in in vivo therapeutic studies. Results: EBRT and MV-NIS were synergistic in vitro. Furthermore, EBRT increased NIS expression in infected cells. SAR-020106 was synergistic with EBRT, but also with MV-NIS in HN5 cells. MV-NIS mediated (131)I-induced cytotoxicity in HN5 and HCT116 cells and, in the latter, this was enhanced by SAR-020106. In vivo studies confirmed that MV-NIS, EBRT and Chk1 inhibition were effective in HCT116 xenografts. The quadruplet regimen of MV-NIS, virally-directed (131)I, EBRT and SAR-020106 had significant anti-tumour activity in HCT116 xenografts. Conclusion: This study strongly supports translational and clinical research on MV-NIS combined with radiation therapy and radiosensitising agents.