911222-45-2 Usage
Description
LY2603618, also known as IC-83, is a potent and selective Checkpoint kinase 1 (Chk1) inhibitor with potential anti-tumor activity. It has an IC50 of 7 nM and is approximately 100-fold more potent against Chk1 than against any other protein kinases evaluated. Chk1 is an important regulator of the DNA damage response, and LY2603618 has been shown to significantly increase tumor growth inhibition when used in combination with other chemotherapeutic agents.
Uses
Used in Oncology:
LY2603618 is used as a chemosensitizer in cancer treatment, enhancing the effectiveness of other chemotherapeutic agents by targeting the DNA damage response. It has been shown to cause a dramatic suppression of cell growth in MCF-7 and MDA-MB-231 human breast cancer cells via Chk1 inhibition-induced upregulation of replication stress caused by oncogenes.
Used in Idiopathic Pulmonary Fibrosis Treatment:
LY2603618 is used as a selective Chk1 inhibitor to treat idiopathic pulmonary fibrosis, a chronic and progressive lung disease characterized by scarring of the lung tissue. By inhibiting Chk1, LY2603618 may help to reduce the fibrosis and improve lung function in patients with this condition.
In vitro
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 vivo
In xenograft models, LY2603618 delays tumor growth when given in combination with pemetrexed.
Biological Activity
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.
in vivo
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].
References
1) King?et al.?(2014),?Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor; Invest. New Drugs,?32?213
2) Calvo?et al.?(2014),?Preclinical analyses and phase I evaluation of LY2603618 administered in combination with pemetrexed and cisplatin in patients with advanced cancer; Invest. New Drugs,?32?955
3) Calvo?et al. (2016),?Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors; Oncology,?91?251
4) Zhao?et al.?(2016),?Inhibition of CHK1 enhances cell death induced by the Bcl-1-selective inhibitor ABT-199 in acute myeloid leukemia cells; Oncotarget,?7?34785
5) Zhang?et al.?(2016),?Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress; Oncotarget,?7?34688
Check Digit Verification of cas no
The CAS Registry Mumber 911222-45-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 9,1,1,2,2 and 2 respectively; the second part has 2 digits, 4 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 911222-45:
(8*9)+(7*1)+(6*1)+(5*2)+(4*2)+(3*2)+(2*4)+(1*5)=122
122 % 10 = 2
So 911222-45-2 is a valid CAS Registry Number.
911222-45-2Relevant articles and documents
HETEROARYL UREA DERIVATIVES USEFUL FOR INHIBITING CHKl
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Page/Page column 90, (2008/06/13)
Substituted urea compounds useful in the treatment of diseases and conditions related to DNA damage or lesions in DNA replication are disclosed. Methods of making the compounds, and their use as therapeutic agents, for example, in treating cancer and other diseases characterized by defects in DNA replication, chromosome segregation, or cell division, also are disclosed.
