Description
LY2603618 (LCI-1) can inhibit CHK1 with IC550 of 7 nM.
Storage
2 years at -20 centigrade
Molecular Formula
C18H22BrN5O3
Chemical Name
(S)-1-(5-bromo-4-methyl-2-(morpholin-2-ylmethoxy)phenyl)-3-(5-methylpyrazin-2-yl)urea
Solubility
DSMO 13 mg/mL Water
In vitro
LY2603618 (LCI-1) is an adenosine triphosphate-competitive inhibitor of Chk1, with IC50 of 7 nM with more than 50-fold selectivity for Chk1 inhibition as compared across a 100-member protein-kinase panel. In cell-based experiments LY2603618 (LCI-1) inhibited doxorubicin-dependent autophosphorylation of Chk1 with IC50 of 52 nM. Treated with 100 nM doxorubicin, HeLa cells arrested at the G2M checkpoint. When treated 24 hours later with LY2603618 (LCI-1), the arrested cells traversed the G2M checkpoint, allowing cells to proceed into mitosis with unresolved replicated chromosomes. Consistent with abrogation of the Chk1-dependent G2M checkpoint, HT-29 cells (mutant p53) treated with LY2603618 (LCI-1) were more sensitiveto killing by gemcitabine then were LY2603618 (LCI-1) treated HCT116 cells(wild-type p53).
In vivo
In vivo, LY2603618 (LCI-1) can effectively inhibit Chk1 autophosphorylation, as well as released the S and G2M block induced by gemcitabinetreatment. When used preclinically in combination with DNA damagingagents, LY2603618 (LCI-1) increased DNA damage and cell death over gemcitabinealone. LY2603618 (LCI-1) shows an effective potentiator of DNA damaging therapies in the clinic. In vivo xenograft studies have demonstrat- ed that LY2603618 in combination with pemetrexed or gemcitabine results in an increase in the antitumor effect compared to that observed in the respective chemotherapeutic agents when administered alone.
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