- METHODS FOR THE TREATMENT OF DISORDERS RELATED TO PHOSPHORYLATION OF HISTONES
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Methods for disease diagnosis, prognosis and therapy selection. Compositions for use in these methods and selected therapies for treatment are also disclosed.
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- CH-01 is a hypoxia-activated prodrug that sensitizes cells to hypoxia/reoxygenation through inhibition of Chk1 and aurora A
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The increased resistance of hypoxic cells to all forms of cancer therapy presents a major barrier to the successful treatment of most solid tumors. Inhibition of the essential kinase Checkpoint kinase 1 (Chk1) has been described as a promising cancer therapy for tumors with high levels of hypoxia-induced replication stress. However, as inhibition of Chk1 affects normal replication and induces DNA damage, these agents also have the potential to induce genomic instability and contribute to tumorigenesis. To overcome this problem, we have developed a bioreductive prodrug, which functions as a Chk1/Aurora A inhibitor specifically in hypoxic conditions. To achieve this activity, a key functionality on the Chk1 inhibitor (CH-01) is masked by a bioreductive group, rendering the compound inactive as a Chk1/Aurora A inhibitor. Reduction of the bioreductive group nitro moiety, under hypoxic conditions, reveals an electron-donating substituent that leads to fragmentation of the molecule, affording the active inhibitor. Most importantly, we show a significant loss of viability in cancer cell lines exposed to hypoxia in the presence of CH-01. This novel approach targets the most aggressive and therapy-resistant tumor fraction while protecting normal tissue from therapy-induced genomic instability.
- Cazares-Koerner, Cindy,Pires, Isabel M.,Swallow, I. Diane,Grayer, Samuel C.,O'Connor, Liam J.,Olcina, Monica M.,Christlieb, Martin,Conway, Stuart J.,Hammond, Ester M.
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p. 1451 - 1459
(2013/08/23)
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- Novel, Cyclically Substituted Furopyrimidine Derivatives and Use Thereof
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The present application relates to novel, cyclically substituted furopyrimidine derivatives, methods for their production, their use for the treatment and/or prophylaxis of diseases and their use for the production of medicinal products for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular diseases.
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- Fused Bicyclic and Tricyclic Pyrimidine Compounds as Tyrosine Kinase Inhibitors
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Fused bicyclic or tricyclic compounds of formula (I): wherein A, B, C, X, Y, m, and n are defined herein. Also disclosed are a method for inhibiting EGFR kinase activity and a method for treating cancer with these compounds.
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Page/Page column 48-49
(2010/06/11)
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- Identification, SAR studies, and X-ray Co-crystallographic analysis of a novel furanopyrimidine aurora kinase a inhibitor
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Herein we reveal a simple method for the identification of novel Aurora kinase A inhibitors through substructure searching of an in-house compound library to select compounds for testing. A hydrazone fragment conferring Aurora kinase activity and heterocy
- Coumar, Mohane Selvaraj,Tsai, Ming-Tsung,Chu, Chang-Ying,Uang, Biing-Jiun,Lin, Wen-Hsing,Chang, Chun-Yu,Chang, Teng-Yuan,Leou, Jiun-Shyang,Teng, Chi-Huang,Wu, Jian-Sung,Fang, Ming-Yu,Chen, Chun-Hwa,Hsu, John T.-A.,Wu, Su-Ying,Chao, Yu-Sheng,Hsieh, Hsing-Pang
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experimental part
p. 255 - 267
(2010/12/18)
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- Synthesis, characterization and antimicrobial evaluation of some arylidenehy drazon of uropyrimidines and thienopyrimidines
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Cyclization of hetcroaromatic o-aminoestcr with formamide afforded furo[2, 3-d]pyrimidin-4(3II)-one which was then chlorinated with thionyl chloride followed by displacement by hydrazine hydrate to furnish hydrazinofuro [2, 3-d]pyrimidine. Reaction of hydrazino derivative with formic acid gave furo[3, 2-c][ 1, 2, 4]triazolo[4, 3-c]pyrimidine. Treatment of hydrazino derivative with aromatic aldehydes afforded arylidenehydrazonofuro[2, 3-d]pyrimidine derivatives. Reaction of o-aminonitrile with carbon disulphide, followed by methylation with methyl iodide and subsequent reaction with hydrazine hydrate afforded hydrazinothieno[2, 3-d]pyrimidine. 14 derivatives were synthesized. Some of these derivatives exhibited pronounced antimicrobial activities against S. typhi, S. aureus, S. dysenteriae, V. cholerae, C. lunata, A. alternata, C. corchori, F. equeseti and M. phaseolina.
- Hossain Bhuiyan, Md. Mosharef,Rahman, Khandker M. M.,Islam, Md. Imjamul
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experimental part
p. 180 - 185
(2010/07/05)
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- FUSED BICYCLIC PYRIMIDINE COMPOUNDS AS AURORA KINASE INHIBITORS
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Fused bicyclic pyrimidine compounds of formula (I): wherein R1, R3, R4, X1, X2, Y, Z, A, B, C, D, n, and the two bonds are defined herein. Also disclosed are a method for inhibiting Aurora kinase activity and a method for treating cancer with these compounds.
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Page/Page column 38
(2009/12/02)
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- Pyrrolopyrimidine derivatives and analogs and their use in the treatment and prevention of diseases
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Described herein are compounds and compositions for modulating kinase activity, and methods for modulating kinase activity using the compounds and compositions. Also described herein are methods of using the compounds and/or compositions in the treatment
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Page/Page column 44
(2010/02/12)
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- Structure-based design of novel Chk1 inhibitors: Insights into hydrogen bonding and protein-ligand affinity
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We report the discovery, synthesis, and crystallographic binding mode of novel furanopyrimidine and pyrrolopyrimidine inhibitors of the Chk1 kinase, an oncology target. These inhibitors are synthetically tractable and inhibit Chk1 by competing for its ATP
- Foloppe, Nicolas,Fisher, Lisa M.,Howes, Rob,Kierstan, Peter,Potter, Andrew,Robertson, Alan G. S.,Surgenor, Allan E.
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p. 4332 - 4345
(2007/10/03)
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