product name LY2603618
Description: LY2603618 (also known as Rabusertib, and IC-83) is a selective Chk1 inhibitor with potential anti-tumor activity in a cell-free assay. LY2603618 binds to and inhibits the activity of chk2, which may prevent the repair of DNA caused by DNA-damaging agents, thus potentiating the antitumor efficacies of various chemotherapeutic agents. Chk2, an ATP-dependent serine-threonine kinase, is a key component in the DNA replication-monitoring checkpoint system and is activated by double-stranded breaks (DSBs); activated chk2 is overexpressed by a variety of cancer cell types.
References: Clin Cancer Res. 2010 Jan 15;16(2):376-83; J Thorac Oncol. 2011 Nov;6(11 Suppl 4):S1757.
436.3
Formula
C18H22BrN5O3
CAS No.
911222-45-2
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 13 mg/mL (29.8 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
2% DMSO+30% PEG400+0.5% Tween80+5% Propylene glycol: 30mg/mL
Synonyms
IC-83
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19406906
| In Vitro |
In vitro activity: Chk1 is an ATP-dependent serine-threonine kinase and a key component in the DNA replication-monitoring checkpoint system activated by double-stranded breaks (DSBs). Chk1 contributes to all currently defined cell cycle checkpoints, including G1/S, intra-S-phase, G2/M, and the mitotic spindle checkpoint. By inhibiting the activity of chk1, LY2603618 prevents the repair of DNA caused by DNA-damaging agents, thus potentiating the antitumor efficacies of various chemotherapeutic agents. However, preclinical data involving LY2603618 has not been published until now. Inhibition of Chk1 is predicted to enhance the effects of antimetabolites, such as gemcitabine. LY2603618 treatment impairs DNA synthesis, increases DNA damage (via mitotic defects), induces apoptosis, and has synergistic activity with pemetrexed, especially in p53 mutant tumor cells. Kinase Assay: Cell Assay: LY2603618 inhibits Chk1 by competing with ATP molecules. In A549 and H1299 non-small cancer cell lines, lethal concentration of LY2603618 (10 µM) not only resulted in cell proliferation arrest (increase population of cell at G2/M phase from 13% to 38%) but also directly DNA damage, the latter of which was indicated by the increasing occurrence of H2AX phosphorylation. |
|---|---|
| In Vivo | In vivo, experiment was carried out to determine the combining effect of LY2603618 with other chemotherapy. In mice xenograft model that inculated with Calu-6 lung cancer cell, combining administration of injected gemcitabine 150 mg/kg and orally uptake LY2603618 (200 mg/kg) resulted in increased DNA damage of tumour, as was demonstrated by a 2-fold increase in Chk1 s345 phosphorylation in comparison with mice treated with gemcitabine alone. |
| Animal model | |
| Formulation & Dosage | |
| References | Clin Cancer Res. 2010 Jan 15;16(2):376-83; J Thorac Oncol. 2011 Nov;6(11 Suppl 4):S1757; Invest New Drugs. 2014 Apr;32(2):213-26. |
