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1.
The EGFR is a validated anticancer target whose successful exploitation has added novel agents to our current treatment protocols. Subsets of patients have shown to benefit the most from these therapies, and though these differential responses have yet to be completely defined, they are mostly of genetic nature. Egfr amplifications have shown to increase sensitivity to both small molecule inhibitors and specific monoclonal antibodies targeting the EGFR. A somatic/germline egfr intron 1 CA repeat sequence polymorphism has shown to have an important role in the control of EGFR protein expression, and has been linked to an increased risk of familial breast cancer, a worse outcome in patients with colorectal cancer, and anti-EGFR treatment efficacy in preclinical models. Egfr activating mutations have been recently described in lung cancer linking a cluster of genotypes with sensitivity to EGFR tyrosine kinase pharmacological inhibition. Despite the initial excitement that this discovery elicited, follow-up reports have not unequivocally confirmed this finding, and these drugs have been solidly efficacious both in individual patients and in diseases generally lacking egfr mutations such as pancreas cancer. We are witnessing exciting developments in the field of the pharmacogenomics of cancer, and this has particularly evolved in the area pertaining EGFR tyrosine kinase inhibitors. This review will discuss the background and currently available preclinical and clinical data. 相似文献
2.
Alec D. Lebsack Bryan J. Branstetter Michael D. Hack Wei Xiao Matthew L. Peterson Nadia Nasser Michael P. Maher Hong Ao Anindya Bhattacharya Mena Kansagara Brian P. Scott Lin Luo Raymond Rynberg Michele Rizzolio Sandra R. Chaplan Alan D. Wickenden J. Guy Breitenbucher 《Bioorganic & medicinal chemistry letters》2009,19(1):40-46
We have identified and synthesized a series of 2,7-diamino-thiazolo[5,4-d]pyrimidines as TRPV1 antagonists. An exploration of the structure–activity relationships at the 2-, 5-, and 7-positions of the thiazolo[5,4-d]pyrimidine led to the identification of several potent TRPV1 antagonists, including 3, 29, 51, and 57. Compound 3 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia with an ED50 = 0.5 mg/kg in rats. 相似文献
3.
Feng Zhao Zhaohu Lin Feng Wang Weili Zhao Xiaochun Dong 《Bioorganic & medicinal chemistry letters》2013,23(19):5385-5388
We report herein the design and synthesis of novel azaspirocycle or azetidine substituted 4-anilinoquinazoline derivatives. The EGFR inhibitory activities and in vitro antitumor potency of these newly synthesized compounds against two lung cancer cell lines HCC827 and A549 were evaluated. Most of the target compounds possess good inhibitory potency. In particular, compounds 21g with 2-oxa-6-azaspiro[3.4]octane substituent was found to possess higher EGFR inhibitory activities and similar antitumor potency comparing to the lead compound gefitinib with improved water solubility. 相似文献
4.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(5):1080-1087
In this study, the synthesis and potential enzyme interactions of new Pyrrolo[2,3-d]pyrimidine derivatives along with their inhibitory activity against SFK enzymes such as Fyn, Lyn, Hck, and c-Src were reported. The results indicated that compounds were slightly active of tested SFK enzymes in comparison with PP2 for Fyn, A-419259 for Lyn and CGP77675 for c-Src. Compound N-((2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl)-4-(3,4-dimethoxyphenyl)butanamide (5) was identified as a non-selective slight inhibitor against Fyn, Lyn and c-Src. However, compounds did not show any inhibitory effects on Hck. Docking studies were performed to analyze the binding mode of compounds against SFKs. The best interaction was obtained between compound 5 and the active site of Fyn and c-Src enzymes in comparison with reference compounds PP2 and CGP77675, respectively. 相似文献
5.
Ducray R Ballard P Barlaam BC Hickinson MD Kettle JG Ogilvie DJ Trigwell CB 《Bioorganic & medicinal chemistry letters》2008,18(3):959-962
Novel 4-anilino-1H-pyrazolo[3,4-d]pyrimidines have been synthesized and evaluated in vitro for erbB2 and EGFR kinase inhibition. A representative compound displaying oral bioavailability in rat and dog illustrates the potential of this series to provide orally active erbB2 inhibitors. 相似文献
6.
Hao Zhang Jin Wang Hong-Yi Zhao Xue-Yan Yang Hao Lei Minhang Xin Yong-Xiao Cao San-Qi Zhang 《Bioorganic & medicinal chemistry》2018,26(12):3619-3633
In the present study, a new class of compounds containing pyrido[3,4-d]pyrimidine scaffold with an acrylamide moiety was designed as irreversible EGFR-TKIs to overcome acquired EGFR-T790M resistance. The most promising compound 25h inhibited HCC827 and H1975 cells growth with the IC50 values of 0.025?μM and 0.49?μM, respectively. Meanwhile, 25h displayed potent inhibitory activity against the EGFRL858R (IC50?=?1.7?nM) and EGFRL858R/T790M (IC50?=?23.3?nM). 25h could suppress EGFR phosphorylation in HCC827 and H1975 cell lines and significantly induce the apoptosis of HCC827 cells. Additionally, compound 25h could remarkably inhibit cancer growth in established HCC827 xenograft mouse model at 50?mg/kg in vivo. These results indicated that the 2,4-disubstituted 6-(5-substituted pyridin-2-amino)pyrido[3,4-d]pyrimidine derivatives can serve as effective EGFR inhibitors and potent anticancer agents. 相似文献
7.
Smith L Wong WC Kiselyov AS Burdzovic-Wizemann S Mao Y Xu Y Duncton MA Kim K Piatnitski EL Doody JF Wang Y Rosler RL Milligan D Columbus J Balagtas C Lee SP Konovalov A Hadari YR 《Bioorganic & medicinal chemistry letters》2006,16(19):5102-5106
Novel tricyclic derivatives containing an oxazepine, thiazepine, or diazepine ring were studied for their EGFR tyrosine kinase inhibitory activity. While the oxazepines were in general more potent than thiazepines, the diazepines displayed somewhat different structure-activity relationships. Moreover, the diazepines, in contrast to the oxazepines, showed appreciable inhibitory activity against the KDR tyrosine kinase. Furthermore, both oxazepines and diazepines demonstrated significant ability to inhibit autophosphorylation of EGFR in DiFi cells (generally, IC(50) values in the single-digit micromolar to submicromolar range). 相似文献
8.
《Bioorganic & medicinal chemistry》2014,22(4):1303-1312
Chromosomal translocations involving anaplastic lymphoma kinase (ALK) are the driving mutations for a range of cancers and ALK is thus considered an attractive therapeutic target. We synthesized a series of functionalized benzo[4,5]imidazo[1,2-c]pyrimidines and benzo[4,5]imidazo[1,2-a]pyrazines by an aza-Graebe–Ullman reaction, followed by palladium-catalyzed cross-coupling reactions. A sequential regioselective cross-coupling route is reported for the synthesis of unsymmetrically disubstituted benzo[4,5]imidazo[1,2-a]pyrazines. The inhibition of ALK was evaluated and compound 19 in particular showed good activity against both the wild type and crizotinib-resistant L1196M mutant in vitro and in ALK-transfected BaF3 cells. 相似文献
9.
Hayakawa M Kaizawa H Moritomo H Koizumi T Ohishi T Yamano M Okada M Ohta M Tsukamoto S Raynaud FI Workman P Waterfield MD Parker P 《Bioorganic & medicinal chemistry letters》2007,17(9):2438-2442
4-Morpholin-4-ylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine 2a was discovered in our chemical library as a novel p110alpha inhibitor with an IC(50) of 1.4 microM. By structural modification of 2a, the 2-aryl-4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidine derivative 10e was discovered as a p110alpha inhibitor with approximately 400-fold greater potency than 2a. Evaluation of isoform selectivity showed that 10e is a potent inhibitor of p110beta. Furthermore, 10e showed anti-proliferative activity in various cell lines, including multi-drug resistant MCF7/ADR-res cells, and was effective against HeLa human cervical tumor xenografts in nude mice. 相似文献
10.
J P Beck M A Curry R J Chorvat L W Fitzgerald P J Gilligan R Zaczek G L Trainor 《Bioorganic & medicinal chemistry letters》1999,9(8):1185-1188
A series of thiazolo[4,5-d]pyrimidine thiones and -ones was prepared and discovered to have good binding affinity to the CRH-R1 receptor, thus showing promise as a new class of potential anxiolytics and/or antidepressants. 相似文献
11.
Hubbard RD Bamaung NY Palazzo F Zhang Q Kovar P Osterling DJ Hu X Wilsbacher JL Johnson EF Bouska J Wang J Bell RL Davidsen SK Sheppard GS 《Bioorganic & medicinal chemistry letters》2007,17(19):5406-5409
A high throughput screen of Abbott's compound repository revealed that the pyrazolo[3,4-d]pyrimidine class of kinase inhibitors possessed moderate potency for IGF-IR, a promising target for cancer chemotherapy. The synthesis and subsequent optimization of this class of compounds led to the discovery of 14, a compound that possesses in vivo IGF-IR inhibitory activity. 相似文献
12.
Smith L Piatnitski EL Kiselyov AS Ouyang X Chen X Burdzovic-Wizemann S Xu Y Pan W Chen X Wang Y Rosler RL Patel SN Chiang HH Milligan DL Columbus J Wong WC Doody JF Hadari YR 《Bioorganic & medicinal chemistry letters》2006,16(6):1643-1646
A novel class of pyrimido[4,5-b]-1,4-benzoxazepines is described as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. Two compounds display potent EGFR inhibitory activity of less than 1 microM in cellular phosphorylation assays (IC(50) 0.47-0.69 microM) and are highly selective against a small kinase panel. Such compounds demonstrate anti-EGFR activity within a class that is different from any known EGFR inhibitor scaffolds. They also provide a basis for the design of kinase inhibitors with the desired selectivity profile. 相似文献
13.
Lingala Suresh P. Sagar Vijay Kumar Y. Poornachandra C. Ganesh Kumar G.V.P. Chandramouli 《Bioorganic & medicinal chemistry letters》2017,27(6):1451-1457
An efficient four-component reaction of 6-amino-1,3-dimethyluracil, N,N-dimethylformamide dimethylacetal, 1-phenyl-3-(4-substituted-phenyl)-4-formyl-1H-pyrazoles and aromatic amines was conducted in the presence of [Bmim]FeCl4 ionic liquid as a promoting medium. This strategy provided a convenient route without any additional catalyst or metal salt under mild conditions. All the synthesized pyrazolo-pyrimido[4,5-d]pyrimidines derivatives were evaluated for their antibacterial, minimum bactericidal concentration (MBC), biofilm inhibition, intracellular ROS accumulation and protein leakage activities. The results revealed that among all the screened derivatives, the compounds 5c, 5i, 5l and 5m were quite promising with MIC values ranging between 3.9 and 15.6 μg/mL, while the MBC values were 2-fold the antibacterial activity values. The biofilm inhibition activity revealed that the compounds 5l and 5 m exhibited promising activity with IC50 values ranging between 1.8 and 8.2 μg/mL. It was observed that at a concentration of 0.5 μg/mL, the compound 5l treated biofilms of Micrococcus luteus showed increased levels of intracellular ROS accumulation. Further, the protein leakage study revealed that the Micrococcus luteus cells treated with compound 5l caused membrane permeability which resulted in protein leakage and subsequent bacterial cell death. 相似文献
14.
Synthesis of [11C]Iressa as a new potential PET cancer imaging agent for epidermal growth factor receptor tyrosine kinase 总被引:1,自引:0,他引:1
Wang JQ Gao M Miller KD Sledge GW Zheng QH 《Bioorganic & medicinal chemistry letters》2006,16(15):4102-4106
Iressa (Gefitinib) is an orally active inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK) involved in cell signal transduction processes critical to proliferation, apoptosis, repair, and angiogenesis of cancer cells. [11C]Iressa was first designed and synthesized as a new potential positron emission tomography (PET) cancer imaging agent for EGFR-TK in 30-40% radiochemical yield with 4.0-6.0 Ci/micromol specific activity at end of bombardment (EOB). 相似文献
15.
A new series of 1,3-thiazoles and thiazolo[4,5-d]pyridazine both bearing the 2-thioureido function were designed, synthesized and evaluated for their in vitro DHFR inhibition and antitumor activities. Compound 26 proved to be the most active DHFR inhibitor (IC50 of 0.06 μM). Compound 4, 20 and 21 showed in vitro antitumor activity against a collection of cancer cell lines. Compound 26 proved lethal to HS 578T breast cancer cell line with IC50 value of 0.8 μM, inducing cell cycle arrest and apoptosis. Molecular modeling studies concluded that recognition with key amino acids Phe 31 and Arg 22 is essential for DHFR binding. The obtained model could be useful for the development of new class of DHFR inhibitors. 相似文献
16.
Sun L Cui J Liang C Zhou Y Nematalla A Wang X Chen H Tang C Wei J 《Bioorganic & medicinal chemistry letters》2002,12(16):2153-2157
A novel class of 4,5-disubstituted-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-ones has been discovered as potent and selective inhibitors of the EGF-R tyrosine kinase family. These compounds selectively inhibit EGF-R kinase activity at low nanomolar concentration and tyrosine autophosphorylation in cells expressing EGF-R or Her2 (p185(erbB)). Structure-activity relationships (SARs) for this class of compounds are presented. 相似文献
17.
A series of new 5-alkyl and 5-arylisoxazolo[4,5-d]pyrimidinones (5a-g, 6-8) were prepared from 4-amino-3-oxo-isoxazolidine-5-carboxylic acid amide. Some of the aryl derivatives of isoxazolo[4,5-d]pyrimidine were tested pharmacologically in comparison with Diazepam. Compounds 5b-d and 7 demonstrated interesting anxiolytic activity. 相似文献
18.
Özadalı K Özkanlı F Jain S Rao PP Velázquez-Martínez CA 《Bioorganic & medicinal chemistry》2012,20(9):2912-2922
In this study, eighteen new isoxazolo[4,5-d]pyridazin-4(5H)-one derivatives possessing either a 1,3,4-thiadiazole or a 1,2,4-triazole-5-thione moiety were synthesized and tested for anti-inflammatory activity in vitro (COX-1/COX-2, 5-LOX) and in vivo (rat paw edema assay). Compounds 15, 16, 25, 26 and 28-30 showed dual COX-2 (IC(50)'s in the 2.1-10.9 μM range), and 5-LOX (IC(50)'s in the 6.3-63.5 μM range) inhibitory activity. When administered orally to rats, dual COX-2/5-LOX inhibitors showed higher anti-inflammatory activity in vivo (30-45% reduction of the inflammatory response) than the reference drug ibuprofen (18%). Among dual COX-2/5-LOX inhibitors, the most potent compound (28) exhibited the best anti-inflammatory profile by inhibiting both COX-2 (IC(50)=2.1 μM) and 5-LOX (IC(50)=6.3 μM) enzymes. We investigated the binding interactions of compound 28 by an enzyme-ligand molecular modeling (docking) studies, which showed favorable binding interactions in both COX-2 and 5-LOX active sites. Furthermore, the dual acting COX-2/5-LOX compound 28 exhibited a superior gastrointestinal safety profile (ulcer index=0.25) compared to the reference drug ibuprofen (UI=7.0) when administered orally at the same molar dose. These observations suggest that isoxazolo[4,5-d]pyridazin-4(5H)-one analogs represent a new scaffold to design potent, effective, and safe anti-inflammatory agents possessing dual COX-2/5-LOX inhibitory activity. 相似文献
19.
Zhao A Gao X Wang Y Ai J Wang Y Chen Y Geng M Zhang A 《Bioorganic & medicinal chemistry》2011,19(13):3906-3918
A series of thieno[2,3-d]pyrimidines and furo[2,3-d]pyrimidines were synthesized and evaluated for the c-Met inhibition. Thieno[2,3-d]pyrimidine 6b stood out as the most potent showing an IC(50) of 35.7 nM. This compound displayed high inhibitory effect on cell proliferation in BaF3-TPR-Met cells and showed high selectivity for c-Met family against other 14 tested kinases. However, compound 6b was found ineffective in the c-Met-dependent U-87MG human gliobastoma xenograft model that may be relevant to its poor PK profile. 相似文献
20.
Gangjee A Namjoshi OA Yu J Ihnat MA Thorpe JE Warnke LA 《Bioorganic & medicinal chemistry》2008,16(10):5514-5528
Direct and indirect involvement of receptor tyrosine kinases (RTKs) in tumor growth and metastasis makes them ideal targets for anticancer therapy. A paradigm shift from inhibition of single RTK to inhibition of multiple RTKs has been recently demonstrated. We designed and synthesized eight N(4)-phenylsubstituted-6-(2-phenylethylsubstituted)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines as homologated series of our previously published RTK inhibitors. We reasoned that increased flexibility of the side chain, which determines potency and selectivity, would improve the spectrum of RTK inhibition. These compounds were synthesized using a bis-electrophilic cyclization to afford substituted pyrrolo[2,3-d]pyrimidines followed by chlorination and substitution at the 4-position with various anilines. Five additional compounds of this series were previously reported by Gangjee et al.(1) with activities against IGFR only. Their synthesis, characterization and biological activities against a variety of other RTKs are reported in this study for the first time. The biological evaluation, in whole cell assays, showed several analogs had remarkable inhibitory activity against epithelial growth factor receptor (EGFR), vascular endothelial growth factor receptor-1 (VEGFR-1), platelet-derived growth factor receptor-beta (PDGFR-beta), the growth of A431 cells in culture, and in the chicken embryo chorioallantoic membrane (CAM) angiogenesis assay. The inhibitory data against the RTKs in this study demonstrate that variation of the 6-ethylaryl substituents as well as the N(4)-phenyl substituents of these analogs does indeed control both the potency and specificity of inhibitory activity against RTKs. In addition, homologation of the chain length of the 6-substituent from a methylene to an ethyl increases the spectrum of RTK inhibition. New multi-RTK inhibitors (8, 12) and potent inhibitors of angiogenesis (15, 19) were identified with the best compound, N(4)-(3-trifluromethylphenyl)-6-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (15), with an IC(50) value of 30nM in the CAM angiogenesis inhibition assay. 相似文献