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Bisarylurea derivatives useful for inhibiting CHK1

An aryl and heteroaryl technology, applied in the field of enzyme-inhibiting compounds, can solve the problems of increasing the sensitivity of the topoisomerase inhibitor BNP1350, exceeding the dose of caffeine, and not being a treatment option

Inactive Publication Date: 2007-07-25
ELI LILLY & CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the dose of caffeine used to achieve cell cycle release exceeds clinically acceptable levels and is not a viable treatment option
In addition, the antisense nucleic acid of Chk1 kinase has been used to increase the sensitivity to the topoisomerase inhibitor BNP1350 (Yin et al., Biochem. Biophys. Res. Commun., 295:435-44, 2002), but also Exhibits problems commonly associated with antisense therapy and gene therapy

Method used

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  • Bisarylurea derivatives useful for inhibiting CHK1
  • Bisarylurea derivatives useful for inhibiting CHK1
  • Bisarylurea derivatives useful for inhibiting CHK1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0351] Determination of ICs for Chk1 inhibitors 50 value

[0352] The cDNA for human Chk1 has been identified and cloned as previously described in International Application Publication No. WO 99 / 11795, filed September 4,1998. A FLAG_tag was inserted in frame at the amino terminus of full-length Chk1. The 5' primer contained an EcoRI site, a Kozak sequence, and also encoded FLAG for affinity purification using the M2 antibody (Sigma, Saint Louis, IL) _ Label. The 3' primer contains a SalI site. The PCR amplified fragment was cloned into pCI-Neo (Invitrogen, Carlsbad, CA) as an EcoRI-SalI fragment and then subcloned into pFastBacI (Gibco-BRL, Bethesda, MD) as an EcoRI-NotI fragment. Recombinant baculoviruses were prepared as described in the Gibco-BRL Bac-to-Bac manual and used to infect Sf-9 cells grown in CCM3 medium (HyClone Laboratories, Logan, UT) to express plus with FLAG _ Tagged Chk1 protein.

[0353] Purification of FLAG-added FLAG from frozen blocks of baculovi...

Embodiment 2

[0356] selectivity

[0357] Relative to one or more other protein kinases, i.e., DNA-PK, Cdc2, casein kinase I (CKI), Chk2, p38 MAP kinase, ERK kinase, protein kinase A (PKA), and / or calcium-calmodulin Protein Kinase II (CaM KII) tests the selectivity of the Chk1 inhibitors of the present invention. With the exception of Chk2, assay procedures for all of these kinases have been previously described in the literature, including US Patent Publication 2002-016521 Al and US Patent Application Serial No. 08 / 184,605, filed January 21, 1994, which are incorporated herein by reference.

[0358] The activity of the compounds on Chk2 was determined as follows: at room temperature, in 4 mM ATP, 1 mCi [ 32 P]γ-ATP, 20mM Hepes pH7.5, 5mM MgCl 2 128 ng of purified His-tagged Chk2 was incubated with up to 100 mM Chk1 inhibitor in the presence of 0.25% NP40 for 20 minutes. The reaction was stopped with phosphoric acid at a final concentration of 150 mM, and 5 / 8 of the reaction mixture wa...

Embodiment 3

[0361] Chk1 inhibitor of the present invention inhibits intracellular Chk1 function

[0362] To determine that a Chk1 inhibitor of the invention inhibits Chk1 function in a cell, the inhibitor can be tested in a cell-based molecular assay. Since mammalian Chk1 has been shown to phosphorylate Cdc25C in vitro, suggesting that it negatively regulates cyclinB / cdc2 in response to DNA damage, Chk1 inhibitors were assayed for their ability to enhance cyclinB / cdc2 activity. The experiment can be designed as follows: BeLa cells are irradiated at 800 rads and incubated at 37°C for 7 hours. Because these cells are negative for p53 function, they only arrest at G2. Next, pyridazole was added to a concentration of 0.5 μg / mL, and the cells were incubated at 37° C. for 15 hours. The purpose of adding pyridazole is to capture any cells that cross the G2 arrest into M. Finally, Chk1 inhibitor was added for 8 hours as suggested by the manufacturer, cells were harvested, lysed and an equiva...

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Abstract

Aryl- and heteroaryl-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. Formula (I).

Description

technical field [0001] The present invention relates to compounds useful for inhibiting enzymes which maintain and restore the integrity of genetic material. More particularly, the present invention relates to a series of aryl- and heteroaryl-substituted urea compounds, methods of making these compounds and their usefulness, for example, in the treatment of cancer and other diseases such as deoxyribonucleic acid (DNA) replication, chromosome segregation or cell division. Use as a therapeutic agent in a disease characterized by defects in . Background technique [0002] A large number of different diseases, conditions and disorders (hereinafter "indications") are characterized by the involvement of abnormally proliferating cells. As used herein, "abnormally proliferating cells" (or "abnormal cell proliferation") refers to cell proliferation that deviates from a normal, appropriate or expected course. For example, abnormal cell proliferation includes inappropriate cell proli...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D241/20C07D405/14A61K31/4965A61P35/00
CPCC07D401/12C07D405/14C07D241/20A61P17/06A61P19/02A61P29/00A61P35/00A61P35/02A61P43/00A61K31/4965
Inventor L·E·伯吉斯A·W·库克K·L·费希尔J·J·高迪诺S·T·施拉赫特尔
Owner ELI LILLY & CO
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