- Design, synthesis and biological evaluation of novel 4-anilinoquinazoline derivatives as hypoxia-selective EGFR and VEGFR-2 dual inhibitors
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Tyrosine kinase inhibitors (TKIs) have achieved substantial clinical effects for cancer treatment while causing a number of adverse effects. Since hypoxia is an intrinsic difference between solid tumor and healthy tissues, one strategy to overcome the adverse effects of TKIs is to enhance the specificity of anti-tumor activity by selectively targeting hypoxic region of tumors. Herein, we designed and synthesized a series of novel 4-anilinoquinazoline derivatives by introducing 3-nitro-1,2,4-triazole group to the side chain of vandetanib with modification of aniline moiety. Lead compounds, 10a and 10g, exhibited potent inhibitory activity against EGFR and VEGFR-2 kinase. Moreover, these two compounds were shown to enhance anti-proliferative activities on A549 and H446 cells under hypoxic conditions compared to vandetanib and dramatically down-regulate VEGF gene expression. In vivo studies confirmed that 10a and 10g not only inhibited tumor growth in A549 xenografts of BALB/c-nu mice but also significantly reduce toxicity associated with weight loss compared to vandetanib. These results suggest that EGFR/VEGFR-2 dual inhibitors, 10a and 10g, emerged as potential hypoxia-selective anti-tumor drugs with less toxicity for inhibiting in vitro and in vivo models of non-small cell lung cancer cells.
- Wei, Huiqiang,Duan, Yuqing,Gou, Wenfeng,Cui, Jie,Ning, Hongxin,Li, Deguan,Qin, Yong,Liu, Qiang,Li, Yiliang
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- 4-Substituted quinazoline derivatives as novel EphA2 receptor tyrosine kinase inhibitors
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Erythropoietin-producing hepatocellular receptor tyrosine kinase subtype A2 (EphA2) is an attractive therapeutic target for suppressing tumor progression. In our efforts to discover novel small molecules to inhibit EphA2, a class of compound based on 4-substituted quinazoline containing 7-(morpholin-2-ylmethoxy) group was identified as a novel hit by high throughput screening campaign. Structural modification of parent quinazoline scaffolds by introducing substituents on aniline displayed potent inhibitory activities toward EphA2.
- Lim, Chae Jo,Oh, Kwang-Seok,Ha, Jae Du,Lee, Jeong Hyun,Seo, Ho Won,Chae, Chong Hack,Kim, Dae-Ghon,Lee, Mi-Jin,Lee, Byung Ho
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p. 4080 - 4083
(2014/09/29)
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- QUINOLINE OR QUINAZOLINE DERIVATIVES WITH APOPTOSIS INDUCING ACTIVITY ON CELLS
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Provided is a pharmaceutical composition comprising, as an active ingredient, a quinoline or quinazoline derivative of formula (I), a pharmaceutically acceptable salt, an isomer, a hydrate, and a solvate thereof, which is effective in the prevention and treatment of a cancer, inflammation, autoimmune diseases or neurodegenerative disorders which are induced by the overexpression of inhibitor of apoptosis proteins (IAPs).
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Page/Page column 52
(2012/03/26)
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- Radiosynthesis of [11C]Vandetanib and [11C]chloro- Vandetanib as new potential PET agents for imaging of VEGFR in cancer
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Vandetanib (ZD6474) and its chlorine analogue chloro-Vandetanib are potent and selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors with low nanomolar IC50 values. [ 11C]Vandetanib and [11C]chloro-Vandetanib, new potential PET agents for imaging of VEGFR in cancer, were first designed, synthesized and labeled at nitrogen and oxygen positions from their corresponding N- and O-des-methylated precursors, in 40-50% decay corrected radiochemical yield and 370-555 GBq/μmol specific activity at end of bombardment (EOB).
- Gao, Mingzhang,Lola, Christian M.,Wang, Min,Miller, Kathy D.,Sledge, George W.,Zheng, Qi-Huang
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experimental part
p. 3222 - 3226
(2011/07/07)
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- SUBSTITUTED QUINAZOLINE INHIBITORS OF GROWTH FACTOR RECEPTOR TYROSINE KINASES
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The present invention relates to new substituted quinazoline inhibitors of vascular endothelial growth factor receptor tyrosine kinase, epidermal growth factor receptor tyrosine kinase, and/or REarranged during Transfection tyrosine kinase, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 16
(2010/04/23)
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- Process for the identification of novel enzyme interacting compounds
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The present invention relates to methods for the characterization of enzymes or of enzyme-compound complexes, wherein the enzyme is obtained from a protein preparation with the help of at least one broad spectrum ligand immobilized on a solid support and wherein the enzyme is characterized by mass spectrometry. These methods are useful for the screening of non-immobilized compound libraries, selectivity profiling of lead compounds and mechanism of action studies in living cells.
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- QUINAZOLINE DERIVATIVES AS INHIBITORS OF VEGF RECEPTOR TYROSINE KINASES
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The present invention relates to compounds of the Formula (I): wherein Z is -NH-, -O- or -S-; R 1 represents bromo or chloro; R 3 represents C 1-3 alkoxy or hydrogen; R 2 is selected from one of the following three groups: (i) Q 1 X 1 - wherein X 1 and Q 1 are as defined herein; (ii) Q 15 W 3 - wherein Q 15 and W 3 are as defined herein; and (iii) Q 21 W 4 C 1-5 alkylX 1 wherein X 1 , W 4 and Q 21 are as defined herein; and salts thereof; their use in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm blooded animals; processes for the preparation of such compounds; pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and methods of treating disease states involving angiogenesis by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compounds of formula (I) inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.
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Page/Page column 75
(2010/02/10)
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- QUINAZOLINE BASED PROTEIN KINASE INHIBITORS
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Hydroxy containing quinazoline based derivatives have enhanced and unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as cancer.
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Page/Page column 16-17; figure 2
(2008/06/13)
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- Design and structure-activity relationship of a new class of potent VEGF receptor tyrosine kinase inhibitors
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A series of substituted 4-anilinoquinazolines and related compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt and KDR) tyrosine kinase activity. Enzyme screening indicated that a narrow structure-activity relationship (SAR) existed for the bicyclic ring system, with quinazolines, quinolines, and cinnolines having activity and with quinazolines and quinolines generally being preferred. Substitution of the aniline was investigated and clearly indicated that small lipophilic substituents such as halogens or methyl were preferred at the C-4' position. Small substituents such as hydrogen and fluorine are preferred at the C-2' position. Introduction of a hydroxyl group at the meta position of the aniline produced the most potent inhibitors of Flt and KDR tyrosine kinases activity with IC50 values in the nanomolar range (e.g. 10, 12, 13, 16, and 18). Investigation of the quinazoline C-6 and C-7 positions indicates that a large range of substituents are tolerated at C-7, whereas variation at the C-6 is more restricted. At C-7, neutral, basic, and heteroaromatic side chains led to very potent compounds, as illustrated by the methoxyethoxy derivative 13 (IC50 2 nM). Our inhibitors proved to be very selective inhibitors of Flt and KDR tyrosine kinase activity when compared to that associated with the FGF receptor (50- to 3800-fold). Observed enzyme profiles translated well with respect to potency and selectivity for inhibition of growth factor stimulated proliferation of human umbilical vein endothelial cells (HUVECs). Oral administration of selected compounds to mice produced total plasma levels 6 h after dosing of between 3 and 49 μM. In vivo efficacy was demonstrated in a rat uterine oedema assay where significant activity was achieved at 60 mg/kg with the meta hydroxy anilinoquinazoline 10. Inhibition of growth of human tumors in athymic mice has also been demonstrated: compound 34 inhibited the growth of established Calu-6 lung carcinoma xenograft by 75% (P 0.001, one tailed t-test) following daily oral administration of 100 mg/kg for 21 days.
- Hennequin, Laurent F.,Thomas, Andrew P.,Johnstone, Craig,Stokes, Elaine S. E.,Plé, Patrick A.,Lohmann, Jean-Jacques M.,Ogilvie, Donald J.,Dukes, Mike,Wedge, Steve R.,Curwen, Jon O.,Kendrew, Jane,Lambert-Van Der Brempt, Christine
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p. 5369 - 5389
(2007/10/03)
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