LY2603618 is a highly selective Chk1 inhibitor with potential anti-tumor activity in a cell-free assay. IC50=7 nM, showing approximately 100-fold more potent against Chk1 than against any of the other protein kinases evaluated.
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.
In xenograft models, LY2603618 delays tumor growth when given in combination with pemetrexed.
LY2603618 (911222-45-2) is a potent (IC50= 7nM) and selective (>1000x over Chk2) Checkpoint kinase 1 (Chk1) inhibitor.1Chk1 is an important regulator of the DNA damage response – combination treatment of LY2603618 with other chemotherapeutic agents significantly increased tumor growth inhibition when compared to chemotherapeutic alone.2,3,4LY2603618 caused a dramatic suppression of cell growth in MCF-7 and MDA-MB-231 human breast cancer cellsviaChk1 inhibition induced upregulation of replication stress caused by oncogenes.5
LY2603618 is a selective Chk1 inhibitor that can treat idiopathic pulmonary fibrosis.
ChEBI: 1-[5-bromo-4-methyl-2-[[(2S)-2-morpholinyl]methoxy]phenyl]-3-(5-methyl-2-pyrazinyl)urea is a member of ureas.
Rabusertib (LY2603618, IC-83) is a highly selective inhibitor of Chk1 with potential antitumor activity in cell-free assays, IC50=7 nM, potency against Chk1 versus multiple other protein kinases tested 100 times higher. Rabusertib (LY2603618) induces cell cycle arrest, DNA damage response and autophagy in cancer cells. Rabusertib (LY2603618) induces bak-dependent apoptosis in AML cell lines.
experiment was carried out to determine the combining effect of ly2603618 with other chemotherapy[2] . 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[2].
[1] CONSTANCE KING. Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor.[J]. Investigational New Drugs, 2014, 32 2: 213-226. DOI:
10.1007/s10637-013-0036-7[2] EMILIANO CALVO. Preclinical analyses and phase I evaluation of LY2603618 administered in combination with pemetrexed and cisplatin in patients with advanced cancer.[J]. Investigational New Drugs, 2014, 32 5: 955-968. DOI:
10.1007/s10637-014-0114-5[3] EMILIANO CALVO. Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors.[J]. Oncology, 2016, 91 5: 251-260. DOI:
10.1159/000448621[4] JIANYUN ZHAO. Inhibition of CHK1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells.[J]. Oncotarget, 2016: 34785-34799. DOI:
10.18632/oncotarget.9185[5] YAO ZHANG. Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress.[J]. Oncotarget, 2016: 34688-34702. DOI:
10.18632/oncotarget.9156
