共查询到20条相似文献,搜索用时 15 毫秒
1.
《Bioorganic & medicinal chemistry letters》2020,30(18):127393
Spleen Tyrosine Kinase (SYK) is a well-studied enzyme with therapeutic applications in oncology and autoimmune diseases. We identified an azabenzimidazole (ABI) series of SYK inhibitors by mining activity data of 86,000 compounds from legacy biochemical assays with SYK and other homologous kinases as target enzymes. A structure-based design and hybridization approach was then used to improve the potency and kinase selectivity of the hits. Lead compound 23 from this novel ABI series has a SYK IC50 = 0.21 nM in a biochemical assay and inhibits growth of SUDHL-4 cells at a GI50 = 210 nM. 相似文献
2.
Sammond DM Nailor KE Veal JM Nolte RT Wang L Knick VB Rudolph SK Truesdale AT Nartey EN Stafford JA Kumar R Cheung M 《Bioorganic & medicinal chemistry letters》2005,15(15):3519-3523
A series of dianilinopyrimidineureas demonstrate potency as VEGFR2 kinase inhibitors. 相似文献
3.
Garofalo A Goossens L Six P Lemoine A Ravez S Farce A Depreux P 《Bioorganic & medicinal chemistry letters》2011,21(7):2106-2112
Three series of 6,7-dimethoxyquinazoline derivatives substituted in the 4-position by aniline, N-methylaniline and aryloxy entities, targeting EGFR and VEGFR-2 tyrosine kinases, were designed and synthesized. Pharmacological activities of these compounds have been evaluated for their enzymatic inhibition of VEGFR-2 and EGFR and for their antiproliferative activities on various cancer cell lines. We have studied the impact of the variation in the 4-position substitution of the quinazoline core. Substitution by aryloxy groups led to new compounds which are selective inhibitors of VEGFR-2 enzyme with IC50 values in the nanomolar range in vitro. 相似文献
4.
Frédéric Gaudette Stéphane Raeppel Hannah Nguyen Normand Beaulieu Carole Beaulieu Isabelle Dupont A. Robert Macleod Jeffrey M. Besterman Arkadii Vaisburg 《Bioorganic & medicinal chemistry letters》2010,20(3):848-852
A novel series of malonamide-type dual VEGFR2/c-Met inhibitors in which one of the amide bonds was replaced by an amide isostere—a trifluoroethylamine unit, was designed, synthesized, and evaluated for their enzymatic and cellular inhibition of VEGFR2 and c-Met enzymes. Optimization of these molecular entities resulted in identification of potent and selective inhibitors of VEGFR2 enzyme. 相似文献
5.
Clémence Feneyrolles Léa Guiet Mathilde Singer Nathalie Van Hijfte Bénédicte Daydé-Cazals Bénédicte Fauvel Gwénaël Chevé Abdelaziz Yasri 《Bioorganic & medicinal chemistry letters》2017,27(4):862-866
AXL is a receptor tyrosine kinase that plays a key role in tumor growth and proliferation. The scientific community has validated AXL as therapeutic target in the treatment of cancers for several years now, and several AXL inhibitors have been developed but none of them are approved. In this context, we started to design new kinase inhibitors targeting AXL from the 7-azaindole scaffold well known to interact with the ATP binding site of the kinase. Focused screening and chemical diversification around 7-azaindole scaffold were developed, based on modeling studies and medicinal chemistry rational, leading to the discovery of a new family of hits with potent inhibitory activity against AXL. 相似文献
6.
RON is a transmembrane receptor tyrosine kinase that mediates biological activities of Macrophage Stimulating Protein (MSP). MSP is a multifunctional factor regulating cell adhesion, motility, growth and survival. MSP binding to RON causes receptor tyrosine phosphorylation leading to up-regulation of RON catalytic activity and subsequent activation of downstream signaling molecules. Recent studies show that RON is spatially and functionally associated with other transmembrane molecules including adhesion receptors integrins and cadherins, and cytokine and growth factor receptors IL-3 betac, EPOR and MET. For example, MSP-induced cell shape change is mediated via RON-activated IL-3 betac receptor. Activation of integrins causes MSP-independent RON phosphorylation, and the integrin/RON collaboration regulates cell survival. Thus, RON can be activated without MSP by ligand stimulation of RON-associated receptors, and MSP-activated RON can cause ligand-independent activation of RON-associated receptors. As a result of the receptor cross-activation RON-specific pathways become a part of a signal transduction network of other receptors, and conversely signaling pathways activated by other receptors can be used by RON. This receptor collaboration extends the spectrum of cellular responses generated by MSP and by putative ligands of RON-associated receptors. However signaling pathways involved in the receptor cross-talk and underlying activation mechanisms remain to be investigated. The purpose of this review is to summarize data and to discuss a role of cross-talk between RON and other transmembrane receptors. 相似文献
7.
Peng H Huang N Qi J Xie P Xu C Wang J Yang C 《Bioorganic & medicinal chemistry letters》2003,13(21):3693-3699
Inhibition of BCR-ABL tyrosine kinase activity has shown to be essential for the treatment of chronic myelogenous leukemia (CML). However, drug resistance has quickly arisen in recent clinical trials for STI571 (Gleevec), which is the first approved drug of CML by inhibiting ABL tyrosine kinase. It is desirable to develop new types of ABL tyrosine kinase inhibitors that may overcome this drug resistance problem. Here we present the discovery of novel inhibitors targeted at the catalytic domain of ABL tyrosine kinase by using three-dimensional database searching techniques. From a database containing 200,000 commercially available compounds, the top 1000 compounds with the best DOCK energy score were selected and subjected to structural diversity and drug likeness analysis, 15 compounds were submitted for biological assay. Eight out of the 15 showed inhibitory activity against K562 cells with IC(50) value ranging from 10 to 200 microM. Two promising compounds showed inhibition in further ABL tyrosine phosphorylation assay. It is anticipated that those two compounds can serve as lead compounds for further drug design and optimization. 相似文献
8.
《Bioorganic & medicinal chemistry letters》2014,24(8):1993-1997
Efforts investigating spatially comparative alternates of the ethylene-bridged piperazine in BMS-791325 that would offer a maintained or improved virologic and pharmacokinetic profile have been multifaceted. One foray involved the utilization of various octahydropyrrolo[3,4-c]pyrrole propellanes. Many of the propellane analogs described in this work exhibited better than targeted potency (less than 20 nM). Additionally, improved exposure in rats was achieved through the employment of two newly invented and now readily accessible carbon bridged propellanes as compared to their heteroatom bridged analogs. 相似文献
9.
Chen S Bartkovitz D Cai J Chen Y Chen Z Chu XJ Le K Le NT Luk KC Mischke S Naderi-Oboodi G Boylan JF Nevins T Qing W Chen Y Wovkulich PM 《Bioorganic & medicinal chemistry letters》2012,22(2):1247-1250
A series of pyrimidodiazepines was identified as potent Polo-like kinase 1 (PLK1) inhibitors. The synthesis and SAR are discussed. The lead compound 7 (RO3280) has potent inhibitory activity against PLK1, good selectivity against other kinases, and excellent in vitro cellular potency. It showed strong antitumor activity in xenograft mouse models. 相似文献
10.
MH Kim AL Tsuhako EW Co DT Aftab F Bentzien J Chen W Cheng S Engst L Goon RR Klein DT Le M Mac JJ Parks F Qian M Rodriquez TJ Stout JH Till KA Won X Wu FM Yakes P Yu W Zhang Y Zhao P Lamb JM Nuss W Xu 《Bioorganic & medicinal chemistry letters》2012,22(15):4979-4985
Variously substituted indolin-2-ones were synthesized and evaluated for activity against KDR, Flt-1, FGFR-1 and PDGFR. Extension at the 5-position of the oxindole ring with ethyl piperidine (compound 7i) proved to be the most beneficial for attaining both biochemical and cellular potencies. Further optimization of 7i to balance biochemical and cellular potencies with favorable ADME/ PK properties led to the identification of 8h, a compound with a clean CYP profile, acceptable pharmacokinetic and toxicity profiles, and robust efficacy in multiple xenograft tumor models. 相似文献
11.
Taisuke Tawaraishi Nobuki Sakauchi Kousuke Hidaka Kyoko Yoshikawa Toshitake Okui Haruhiko Kuno Ikumi Chisaki Kazuyoshi Aso 《Bioorganic & medicinal chemistry letters》2018,28(18):3067-3072
CCR6 has been implicated in both autoimmune diseases and non-autoimmune diseases. Thus, inhibition of CCR6-dependent cell migration is an attractive strategy for their treatment. An orally available small molecule inhibitor of CCR6 could therefore be a useful biological probe for the pathophysiological studies. Initial SAR study of a hit compound provided potent N-benzenesulfonylpiperidine derivatives that suppressed CCL20-induced Gi signals. By subsequent scaffold morphing of the central ring and further optimization, we identified a novel series of 1,4-trans-1-benzenesulfonyl-4-aminocyclohexanes as potent and selective CCR6 inhibitors with good pharmacokinetic properties. Our compounds showed good correlation between Gi signal inhibitory activity and cell migration inhibitory activity in human CCR6-transfected CHO cells. In addition, representative compound 35 potently inhibited CCR6-dependent cell migration and the increase in ERK phosphorylation in human primary cells. Therefore, the compound could be used effectively as a biological probe against human CCR6. 相似文献
12.
RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP. 总被引:22,自引:1,他引:21 下载免费PDF全文
G Gaudino A Follenzi L Naldini C Collesi M Santoro K A Gallo P J Godowski P M Comoglio 《The EMBO journal》1994,13(15):3524-3532
13.
Barlaam B Ballard P Bradbury RH Ducray R Germain H Hickinson DM Hudson K Kettle JG Klinowska T Magnien F Ogilvie DJ Olivier A Pearson SE Scott JS Suleman A Trigwell CB Vautier M Whittaker RD Wood R 《Bioorganic & medicinal chemistry letters》2008,18(2):674-678
Starting from initial lead 1 containing a basic 5-substituent, optimisation of the glycolamide-derived neutral 5-substituent led to potent inhibitors of erbB2 with good pharmacokinetics. Representative compounds 19 and 21 inhibited phosphorylation of erbB2 in a mouse BT474C xenograft model after oral administration. 相似文献
14.
RON (Recepteur d’Origine Nantais) tyrosine kinase receptor is a promising target for therapeutic intervention in cancer therapy. The aim of this work was identification of RON-binding peptides using phage display and computational modeling their mode of binding. A 12-mer peptide phage library was utilized to perform biopanning against RON. The RON-binding ability of the selected peptide-displaying phage and their possible binding sites were examined by ELISA. Binding modes and affinities were also predicted by docking and molecular dynamics (MD) simulation. The results of ELISA experiment showed that P6 peptide displaying phage has higher affinity for RON compared to others and its binding site is located out of ligand binding site. Docking and MD simulation results also indicated higher affinity of P6 to RON as well as its exosite-binding feature. Taken together, our data suggest a capacity for P6 peptide (FEHSLYKEMTHL) to be utilized as RON binding agent, and hence be used for various purposes, including design of drug delivery systems for transferring cytotoxic agents to RON-positive cancer cells, interfering with RON signaling, peptidomimetics design, and diagnostic imaging. 相似文献
15.
A series of imidazole flavonoids as new type of protein tyrosine phosphatase inhibitors were synthesized and characterized. Most of them gave potent protein phosphatase 1B (PTP1B) inhibitory activities. Especially, compound 11a could effectively inhibit PTP1B with an IC50 value of 0.63 μM accompanied with high selectivity ratio (9.5-fold) over T-cell protein tyrosine phosphatase (TCPTP). This compound is cell permeable with relatively low cytotoxicity. The high binding affinity and selectivity was disclosed by molecular modeling and dynamics studies. The structural features essential for activity were confirmed by quantum chemical studies. 相似文献
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17.
Chih-Hung Chen On Lee Chung-Niang Yao Meng-Yun Chuang Yow-Lone Chang May-Hua Chang Yen-Fang Wen Wan-Hsu Yang Ching-Huai Ko Nien-Tzu Chou Mai-Wei Lin Chin-Pen Lai Chung-Yuan Sun Ling-mei Wang Yen-Chun Chen Tzong-Hsiung Hseu Chia-Ni Chang Hui-Chun Hsu Hui-Chi Lin Yu-Li Chang Chrong-Shiong Hwang 《Bioorganic & medicinal chemistry letters》2010,20(20):6129-6132
A series of azulene-based derivatives were synthesized as potent inhibitors for receptor tyrosine kinases such as FMS-like tyrosine kinase 3 (FLT-3). Systematic side chain modification of prototype 1a was carried out through SAR studies. Analogue 22 was identified from this series and found to be one of the most potent FLT-3 inhibitors, with good pharmaceutical properties, superior efficacy, and tolerability in a tumor xenograft model. 相似文献
18.
《Bioorganic & medicinal chemistry letters》2014,24(17):4080-4083
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. 相似文献
19.