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Rabusertib

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Chemical Structure| 911222-45-2 同义名 : LY2603618;IC-83
CAS号 : 911222-45-2
货号 : A141550
分子式 : C18H22BrN5O3
纯度 : 99%+
分子量 : 436.303
MDL号 : MFCD18633253
存储条件：

粉末 Keep in dark place,Sealed in dry,Store in freezer, under -20°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 30 mg/mL(68.76 mM)，配合低频超声，并水浴加热至45℃助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：
生物活性
靶点

  • Chk1

    Chk1, IC50:7 nM
描述 Chk1 (Checkpoint kinase 1), an important serine/threonine kinase, is responding to DNA damage and stall DNA replication. Chk1 plays a key role in maintaining the replication fork viability during exposure to DNA antimetabolites. Inhibition of Chk1 will lead to accumulation of double-strand DNA breaks and cell death in human tumor cell lines exposure to antimetabolite. LY2603618 (Rabusertib) is a selective inhibitor of Chk1 with IC50 value of 7nM (measured by protein kinase assays). Treatment with 14-3300nM LY2603618 for 2h can dose-dependently decrease the level of phosphorylated Chk1 serine 296, an autophosphorylation reflecting Chk1 catalytic activity, in HeLa cells incubated with 100nM doxorubicin for 24h. Similar result can also be obtained in Calu6 Cells treated with 60nM gemcitabine. After treatment with LY2603618 1250 or 5000nM for 24h, increased level of p-H2A.X-S139 and p-H3-S10, the markers of DNA damage and mitotic, can be observed in HeLa cells. Meanwhile, a clear decrease in the G1 population and an increase in late S-phase cells, as well as cell arrest in an aberrant prometaphase state by LY2603618 can be observed. These indicated that inhibition of Chk1 by LY2603618 can abrogate the S-phase checkpoint. An increase in staining of the mitotic marker p-H3-Ser10 can be observed in HeLa cells treated for 24h with 100nM doxorubicin to cause a G2 arrest, then for 7h with serially diluted LY2603618. This indicated that LY2603618 can inactivate the G2/M DNA damage checkpoint[1]. Combining 200mg/kg of LY2603618 with 160mg/kg of gemcitabine increased the tumor growth delay compared with gemcitabine alone in Calu-6 and HT-29 xenograft tumor models[2]. Up to now, phase 2 studies of LY2603618 treatment for non small cell lung cancer and pancreatic neoplasms have been completed (see https://www.clinicaltrials.gov/).
作用机制 LY2603618 bound in the ATP binding site of Chk1.
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
A549 ~10 μM Function assay induces cell cycle arrest 24928205
A549 ~20 μM Function assay activates DNA damage sensor kinases 24928205
A549 ~20 μM Apoptosis assay induces apoptosis 24928205
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.29mL

0.46mL

0.23mL

11.46mL

2.29mL

1.15mL

22.92mL

4.58mL

2.29mL
参考文献

[1]King C, Diaz H, et al. Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor. Invest New Drugs. 2014 Apr;32(2):213-26.

[2]Barnard D, Diaz HB, et al. LY2603618, a selective CHK1 inhibitor, enhances the anti-tumor effect of gemcitabine in xenograft tumor models. Invest New Drugs. 2016 Feb;34(1):49-60.