"目錄號(hào): HY-14720

Cell Cycle/DNA DamageAutophagy-

LY2603618 是一種有效的選擇性的Chk1抑制劑，IC50為 7 nM。

Checkpoint Kinase (Chk)Autophagy

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生物活性

Description

LY2603618 is a potent and selective inhibitor ofChk1protein kinase activity in vitro withIC50of 7 nM.

IC50& Target

IC50: 7 nM (Chk1)[1]

In Vitro

LY2603618 is a highly effective inhibitor of multiple aspects of Chk1 biology. LY2603618 is tested against a panel of 51 diverse protein kinases in vitro. With an IC50of 7 nM for Chk1, LY2603618 is approximately 100-fold more potent against Chk1 than against any of the other protein kinases evaluated (PDK1, IC50=893 nM, others >1000 nM). LY2603618 effectively reduced Chk1 autophosphorylation with an EC50of 430 nM. Inhibition of Chk1 by LY2603618 also effectively abrogated the G2/M DNA damage checkpoint in cells treated with DNA damaging agents. Treatment of cells with LY2603618 produced a cellular phenotype similar to that reported for depletion of Chk1 by RNAi. Inhibition of intracellular Chk1 by LY2603618 results in impaired DNA synthesis, elevated H2A.X phosphorylation indicative of DNA damage and premature entry into mitosis[1]. Treatments of the SK-N-BE(2) cells with variable concentrations of LY2603618 results in dose-dependent inhibition of cell growth determined by MTT assays with an IC50of 10.81 μM[1].

In Vivo

Mice bearing Calu-6 xenografts are treated with 150 mg/kg (IP) Gemcitabine and a single simultaneous 200 mg/kg oral dose of LY2603618. 200 mg/kg of LY2603618 is sufficient to inhibit 85 % of Chk1 autophosphorylation in vivo at 2 h. LY2603618 effectively reduces Gemcitabine-induced phosphorylation on Tlk serine 695 as well, supporting the cited report with a selective chemical inhibitor of Chk1[1].

Clinical Trial

NCT01358968

Eli Lilly and Company

Cancer

June 2011

Phase 1

NCT01341457

Eli Lilly and Company

Solid Tumors

May 2011

Phase 1

NCT01296568

Eli Lilly and Company

Advanced Cancer

February 2011

Phase 1

NCT00415636

Eli Lilly and Company

Cancer

December 2006

Phase 1

NCT00839332

Eli Lilly and Company

Pancreatic Neoplasms

March 2009

Phase 1-Phase 2

NCT01139775

Eli Lilly and Company

Non Small Cell Lung Cancer

February 2011

Phase 1-Phase 2

NCT00988858

Eli Lilly and Company

Non Small Cell Lung Cancer

November 2009

Phase 2

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References

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

[2].Wang G, et al. Panobinostat synergistically enhances the cytotoxic effects of cisplatin, doxorubicin or etoposide on high-risk neuroblastoma cells. PLoS One. 2013 Sep 30;8(9):e76662.