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1.
A Dual Non‐ATP Analogue Inhibitor of Aurora Kinases A and B,Derived from Resorcinol with a Mixed Mode of Inhibition 下载免费PDF全文
Dhanasekaran Karthigeyan Sudhevan Surabhi Pushpak Mizar Siddhanta Soumik Amrita Banerjee Sarmistha Halder Sinha Dipak Dasgupta Chandrabhas Narayana Tapas K. Kundu 《Chemical biology & drug design》2016,87(6):958-967
Aurora kinases are the most commonly targeted mitotic kinases in the intervention of cancer progression. Here, we report a resorcinol derivative, 5‐methyl‐4‐(2‐thiazolylazo) resorcinol (PTK66), a dual inhibitor of Aurora A and Aurora B kinases. PTK66 is a surface binding non‐ATP analogue inhibitor that shows a mixed pattern of inhibition against both of Aurora A and B kinases. The in vitro IC50 is approximately 47 and 40 μm for Aurora A and Aurora B kinases, respectively. In cellular systems, PTK66 exhibits a substantially low cytotoxicity at micromolar concentrations but it can induce aneuploidy under similar dosages as a consequence of Aurora kinase inhibition. This result was corroborated by a drop in the histone H3 (S10) phosphorylation level detected via Western blot analysis using three different cell types. Altogether, our findings indicate that the ligand containing resorcinol backbone is one of the novel scaffolds targeting the Aurora family of kinases, which could be a target for antineoplastic drug development. 相似文献
2.
An update on the pharmacokinetics and pharmacodynamics of alisertib,a selective Aurora kinase A inhibitor 下载免费PDF全文
Cameron T Durlacher Zhi‐Ling Li Xiao‐Wu Chen Zhi‐Xu He Shu‐Feng Zhou 《Clinical and experimental pharmacology & physiology》2016,43(6):585-601
Human Aurora kinases, including Aurora kinase A (AURKA), B (AURKB), and C (AURKC), play an essential role in mitotic events such as monitoring of the mitotic checkpoint, creation of bipolar mitotic spindle and alignment of centrosomes on it, also regulating centrosome separation, bio‐orientation of chromosomes and cytokinesis. AURKA and AURKB are key regulators of mitosis and centrosome via polymerizing microfilaments and controlling chromatid segregation. In particular, AURKA plays critical roles in the regulation of mitotic entry, centrosome function, bipolar spindle assembly, and chromosome segregation. AURKA has been found to be overexpressed in various solid and haematological cancers and has been linked with poor prognosis. Its important role in cancer initiation, growth, and metastasis has brought the focus to search for potent and selective AURKA inhibitors for cancer treatment. MLN8237, also known as alisertib, is one selective AURKA inhibitor that has shown remarkable anticancer effects in preclinical studies. Alisertib exhibits favourable pharmacokinetic properties. Alisertib has generally showed good partial response rates of 4–52% and good safety profiles in Phase I and II trials when it is solely administered as well as combined with cytotoxic chemotherapeutic drugs. Recently, the multicentre, randomized Phase III study of alisertib in patients with relapsed or refractory peripheral T‐cell lymphoma has been discontinued due to unsatisfactory efficacy. The low risk of side effects, accessibility, and effectiveness of alisertib makes it a new promising anticancer therapy and further mechanistic and clinical studies are warranted. 相似文献
3.
Hui‐Yuan Wang Lin‐Li Li Zhi‐Xing Cao Shi‐Dong Luo Yu‐Quan Wei Sheng‐Yong Yang 《Chemical biology & drug design》2009,73(1):115-126
In this study, 3D‐pharmacophore models of Aurora B kinase inhibitors have been developed by using HipHop and HypoGen modules in Catalyst software package. The best pharmacophore model, Hypo1, which has the highest correlation coefficient (0.9911), consists of one hydrogen‐bond acceptor, one hydrogen‐bond donor, one hydrophobic aliphatic moiety and one ring aromatic feature. Hypo1 was validated by test set and cross‐validation methods. And the specificity of Hypo1 to Aurora B inhibitors was examined with the use of selective inhibitors against Aurora B and its paralogue Aurora A. The results clearly indicate that Hypo1 can differentiate selective inhibitors of Aurora B from those of Aurora A, and the ring aromatic feature likely plays some important roles for the specificity of Hypo1. Then Hypo1 was used as a 3D query to screen several databases including Specs, NCI, Maybridge and Chinese Nature Product Database (CNPD) for identifying new inhibitors of Aurora B. The hit compounds were subsequently subjected to filtering by Lipinski’s rule of five and docking studies to refine the retrieved hits, and some compounds selected from the top ranked hits have been suggested for further experimental assay studies. 相似文献
4.
Ming Zheng Youguang Zheng Yunsheng Xue Yi Liu Lin An Ling Zhang Min Ji Bai Xue Xuan Wu Xuedong Gong Ning Gu Xi Zhan 《Chemical biology & drug design》2013,81(3):399-407
Nine novel 4‐aminoquinazoline derivatives were designed and synthesized. Biochemical and cellular analyses demonstrated that most of the derivatives exhibited a strong activity to inhibit Aurora A and B kinases and to suppress the proliferation of a panel of human tumor cell lines (U937, K562, A549, LoVo, and HT29). Quantum chemical studies were also carried out to determine the structural features of these compounds engaged in the inhibition of Aurora kinases. 相似文献
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Characterization of a Pyrazolo[4,3‐d]pyrimidine Inhibitor of Cyclin‐Dependent Kinases 2 and 5 and Aurora A With Pro‐Apoptotic and Anti‐Angiogenic Activity In Vitro 下载免费PDF全文
Eva Řezníčková Sabine Weitensteiner Libor Havlíček Radek Jorda Tomáš Gucký Karel Berka Václav Bazgier Stefan Zahler Vladimír Kryštof Miroslav Strnad 《Chemical biology & drug design》2015,86(6):1528-1540
Selective inhibitors of kinases that regulate the cell cycle, such as cyclin‐dependent kinases (CDKs) and aurora kinases, could potentially become powerful tools for the treatment of cancer. We prepared and studied a series of 3,5,7‐trisubstituted pyrazolo[4,3‐d]pyrimidines, a new CDK inhibitor scaffold, to assess their CDK2 inhibitory and antiproliferative activities. A new compound, 2i , which preferentially inhibits CDK2, CDK5, and aurora A was identified. Both biochemical and cellular assays indicated that treatment with compound 2i caused the downregulation of cyclins A and B, the dephosphorylation of histone H3 at Ser10, and the induction of mitochondrial apoptosis in the HCT‐116 colon cancer cell line. It also reduced migration as well as tube and lamellipodia formation in human endothelial cells. The kinase inhibitory profile of compound 2i suggests that its anti‐angiogenic activity is linked to CDK5 inhibition. This dual mode of action involving apoptosis induction in cancer cells and the blocking of angiogenesis‐like activity in endothelial cells offers possible therapeutic potential. 相似文献
7.
Prakash J de Borst MH van Loenen-Weemaes AM Lacombe M Opdam F van Goor H Meijer DK Moolenaar F Poelstra K Kok RJ 《Pharmaceutical research》2008,25(10):2427-2439
Purpose Activation of tubular epithelial cells by transforming growth factor-beta (TGF-β) plays an important role in the pathogenesis
of renal tubulointerstitial fibrosis. We developed a renally accumulating conjugate of a TGF-β type-I receptor kinase inhibitor
(TKI) and evaluated its efficacy in vitro and in vivo.
Methods TKI was conjugated to the protein Lysozyme (LZM) via a platinum-based linker. TKI-LZM was evaluated in human tubular cells
(HK-2) for its anti-fibrotic activity. Plasma, kidney and urine drug levels after a single intravenous dose of TKI-LZM in
rats were determined by HPLC or immunodetection. Anti-fibrotic effects of TKI-LZM were examined in the unilateral ureteral
obstruction (UUO) model.
Results TKI-LZM conjugate was successfully synthesized at an 1:1 drug/carrier ratio, and inhibited TGF-β1-induced procollagen-1α1
gene expression in HK-2 cells. In vivo, TKI-LZM accumulated rapidly in tubular cells and provided a local depot for 3 days. Interestingly, a single dose of TKI-LZM
inhibited the activation of tubular cells and fibroblasts in UUO rats and reduced renal inflammation. In contrast, free TKI
at an equimolar (low) dosage exhibited little effects.
Conclusions Inhibition of TGF-beta signaling by local drug delivery is a promising antifibrotic strategy, and demonstrated the important
role of tubular activation in renal fibrosis. 相似文献
8.
Curtis J. Henrich Anuradha Budhu Zhipeng Yu Jason R. Evans Ekaterina I. Goncharova Tanya T. Ransom Xin W. Wang James B. McMahon 《Chemical biology & drug design》2013,82(2):131-139
The cancer stem cell marker, EpCAM, is an important indicator of Wnt/β‐catenin signaling activation and a functional component of hepatocellular tumor‐initiating cells. A high‐throughput screening assay was developed to identify inhibitors of EpCAM‐dependent growth of hepatocellular carcinoma (HCC) cells. EpCAM(+) and EpCAM(?) HCC cell lines were assessed for differential sensitivity to a Wnt/β‐catenin pathway inhibitor. Libraries comprising 22 668 pure compounds and 107 741 crude or partially purified natural product extracts were tested, and 12 pure compounds and 67 natural product extracts were identified for further study. Three active compounds and the positive control were further characterized in terms of effects on EpCAM expression. Treatment of EpCAM(+) Hep3B cells resulted in loss of EpCAM expression as assessed by flow cytometry. This reduction was incomplete (most cells continued to express EpCAM), but resulted in generation of cell populations expressing lower levels of EpCAM. Sublethal concentrations (~IC50) reduced median EpCAM expression to 28% of control after 1 day and 19% of control after 2 days. Reduction in EpCAM expression preceded growth inhibition suggesting that a threshold of EpCAM expression may be required for growth of EpCAM‐dependent cells. The identification of compounds with a variety of possible molecular targets suggests a likelihood of multiple mechanisms for modulation of EpCAM‐dependent cell growth. 相似文献
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AM‐694 (1‐[(5‐fluoropentyl)‐1H‐indol‐3‐yl]‐(2‐iodophenyl)methanone), a synthetic indole‐based cannabimimetic, was first reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) via the Early Warning System (EWS) by Irish authorities in 2010. Using gas chromatography–mass spectrometry (GC‐MS), we have identified six AM‐694 metabolites in post‐ingestion samples. The metabolites were tentatively identified as products of (1) hydrolytic defluorination, (2) carboxylation, (3) monohydroxylation of N‐alkyl chain, and (4) hydrolytic defluorination combined with monohydroxylation of N‐alkyl chain. The parent compound was not detected. The excretion of major metabolites was observed up to 117 h following administration. One metabolite (a product of hydrolytic defluorination) was also identified in urine samples from two individuals admitted to hospital suffering from suspected drug overdoses. Copyright © 2012 John Wiley & Sons, Ltd. 相似文献
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Apocynin Suppresses Lipopolysaccharide‐Induced Inflammatory Responses Through the Inhibition of MAP Kinase Signaling Pathway in RAW264.7 Cells 下载免费PDF全文
Young‐Jae Hwang Sung Joon Lee Jin‐Young Park Wanjoo Chun Seung‐Joo Nam Jin Myung Park Sung Chul Park Dae Hee Choi Chang Don Kang 《Drug development research》2016,77(6):271-277
13.
目的 探讨聚维酮(PVP)对人膀胱癌T24细胞的抑制作用。 方法 采用MTT法检测PVP对T24细胞生长的抑制作用,流式细胞仪检测PVP对T24细胞周期的影响和黏附作用。结果 2.5%PVP作用24和72 h,对人膀胱癌T24细胞生长抑制率分别为(15.11±2.36)%和(49.57±7.07)%;浓度为7.5%时24和72 h抑制率分别(35.42±5.55)%和(79.66±19.92)%。5.0%PVP作用24和72 h时,细胞G0/G1期所占比例分别为(74.17±0.91)%和(46.69±3.76)%;G2/M期细胞所占比例分别为(14.63±0.47)%和(41.88±1.50)%。PVP能提高抗鼠IgG1对T24细胞的黏附作用。结论 PVP能通过诱导人膀胱癌T24细胞周期阻滞于G2/M期和作为化疗药的黏附性载体而抑制癌细胞的生长增殖。 相似文献
14.
目的:研究磷脂酰肌醇3-激酶(PI3K)抑制剂LY29400(简称LY)联合吲哚-3-甲醇(I3C)对人甲状腺未分化癌细胞FRO增殖的抑制作用。方法:取对数生长期FRO细胞,分为空白对照组、I3C(250μmol/L)组、LY(10μmol/L)组和联用(I3C 250μmol/L+LY 10μmol/L)组,药物作用24、48、72 h。采用MTT法测定并计算各组细胞的增殖抑制率;流式细胞术检测作用48 h后的细胞凋亡率;Western blot法检测作用48 h后半胱氨酸天冬氨酸蛋白酶3(Caspase-3)蛋白的表达;免疫组化法检测作用48 h后Bcl-2、Bax蛋白的表达。结果:细胞增殖抑制率随药物作用时间的延长而明显升高,联用组各时间点间差异具有统计学意义(P<0.05)。与I3C组和LY组比较,联用组细胞的增殖抑制率、细胞凋亡率和Caspase-3、Bax蛋白表达均增强,Bcl-2蛋白表达和Bcl-2/Bax均降低,差异有统计学意义(P<0.01)。结论:LY与I3C联用对FRO细胞的增殖具有协同抑制作用,其机制可能与下调Bcl-2表达、上调Bax表达、激活Caspase级联反应诱导细胞凋亡有关。 相似文献
15.
Site‐directed Mutagenesis of Key Residues Unveiled a Novel Allosteric Site on Human Adenosine Kinase for Pyrrolobenzoxa(thia)zepinone Non‐Nucleoside Inhibitors 下载免费PDF全文
Lida Savi Margherita Brindisi Gloria Alfano Stefania Butini Valeria La Pietra Ettore Novellino Luciana Marinelli Andrea Lossani Federico Focher Caterina Cavella Giuseppe Campiani Sandra Gemma 《Chemical biology & drug design》2016,87(1):112-120
Most nucleoside kinases, besides the catalytic domain, feature an allosteric domain which modulates their activity. Generally, non‐substrate analogs, interacting with allosteric sites, represent a major opportunity for developing more selective and safer therapeutics. We recently developed a series of non‐nucleoside non‐competitive inhibitors of human adenosine kinase (hAK), based on a pyrrolobenzoxa(thia)zepinone scaffold. Based on computational analysis, we hypothesized the existence of a novel allosteric site on hAK, topographically distinct from the catalytic site. In this study, we have adopted a multidisciplinary approach including molecular modeling, biochemical studies, and site‐directed mutagenesis to validate our hypothesis. Based on a three‐dimensional model of interaction between hAK and our molecules, we designed, cloned, and expressed specific, single and double point mutants of hAK (Q74A, Q78A, H107A, K341A, F338A, and Q74A‐F338A). Kinetic characterization of recombinant enzymes indicated that these mutations did not affect enzyme functioning; conversely, mutated enzymes are endowed of reduced susceptibility to our non‐nucleoside inhibitors, while maintaining comparable affinity for nucleoside inhibitors to the wild‐type enzyme. This study represents the first characterization and validation of a novel allosteric site in hAK and may pave the way to the development of novel selective and potent non‐nucleoside inhibitors of hAK endowed with therapeutic potential. 相似文献
16.
para‐Phenylenediamine induces apoptosis through activation of reactive oxygen species‐mediated mitochondrial pathway,and inhibition of the NF‐κB,mTOR, and Wnt pathways in human urothelial cells 下载免费PDF全文
Kasi Reena Khuen Yen Ng Rhun Yian Koh Ponnudurai Gnanajothy Soi Moi Chye 《Environmental toxicology》2017,32(1):265-277
para‐Phenylenediamine (PPD) has long been used in two‐thirds of permanent oxidative hair dye formulations. Epidemiological studies and in vivo studies have shown that hair dye is a suspected carcinogen of bladder cancer. However, the toxicity effects of PPD to human bladder remains elusive. In this study, the effects of PPD and its involvement in the apoptosis pathways in human urothelial cells (UROtsa) was investigated. It was demonstrated that PPD decreased cell viability and increased the number of sub‐G1 hypodiploid cells in UROtsa cells. Cell death due to apoptosis was detected using Annexin V binding assay. Further analysis showed PPD generated reactive oxygen species (ROS), induced mitochondrial dysfunction through the loss of mitochondrial membrane potential and increased caspase‐3 level in UROtsa cells. Western blot analysis of PPD‐treated UROtsa cells showed down‐regulation of phosphorylated proteins from NF‐κB, mTOR, and Wnt pathways. In conclusion, PPD induced apoptosis via activation of ROS‐mediated mitochondrial pathway, and possibly through inhibition of NF‐κB, mTOR, and Wnt pathways. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 265–277, 2017. 相似文献
17.
Umasankar De Soma Kundu Nabanita Patra Mee Young Ahn Ji Hae Ahn Ji Yeon Son Jung Hyun Yoon Hyung Ryoung Moon Byung Mu Lee Hyung Sik Kim 《Biomolecules & therapeutics.》2015,23(5):434-441
Histone deacetylase (HDAC) inhibitors are considered novel agents for cancer chemotherapy. We previously investigated MHY219, a new HDAC inhibitor, and its potent anticancer activity in human prostate cancer cells. In the present study, we evaluated MHY219 molecular mechanisms involved in the regulation of prostate cancer cell migration. Similar to suberanilohydroxamic acid (SAHA), MHY219 inhibited HDAC1 enzyme activity in a dose-dependent manner. MHY219 cytotoxicity was higher in LNCaP (IC50=0.67 μM) than in DU145 cells (IC50=1.10 μM) and PC3 cells (IC50=5.60 μM) after 48 h of treatment. MHY219 significantly inhibited the HDAC1 protein levels in LNCaP and DU145 cells at high concentrations. However, inhibitory effects of MHY219 on HDAC proteins levels varied based on the cell type. MHY219 significantly inhibited LNCaP and DU145 cells migration by down-regulation of matrix metalloprotease-1 (MMP-1) and MMP-2 and induction of tissue inhibitor of metalloproteinases-1 (TIMP-1). These results suggest that MHY219 may potentially be used as an anticancer agent to block cancer cell migration through the repression of MMP-1 and MMP-2, which is related to the reduction of HDAC1. 相似文献
18.
Baicalein Induces Caspase‐dependent Apoptosis Associated with the Generation of ROS and the Activation of AMPK in Human Lung Carcinoma A549 Cells 下载免费PDF全文
Hong Jae Kim Cheol Park Min‐Ho Han Su‐Hyun Hong Gi‐Young Kim Sang Hoon Hong Nam Deuk Kim Yung Hyun Choi 《Drug development research》2016,77(2):73-86
Preclinical Research |
19.
Swati S. Chitnis Chellasamy Selvaakumar Dhanashree D. Jagtap Ravi P. Barnwal Kandala V. R. Chary Smita D. Mahale Tarala D. Nandedkar 《Chemical biology & drug design》2009,73(6):637-643
Follicle‐stimulating hormone (FSH) receptor binding inhibitor (FRBI‐8) is a novel octapeptide purified from human ovarian follicular fluid. In vitro, it inhibits the binding of FSH to granulosa cells and in vivo, it induces atresia in developing follicles in rodents. This peptide, when administered to marmosets and bonnet monkeys, altered the circulating progesterone levels. This study was carried out to elucidate structure of the FRBI‐8 and understand its mechanism of inhibiting interaction of FSH to its receptors. Homology modeling predicted that the FRBI‐8 adopts a turn and random coil. This is further confirmed by circular dichroism and NMR. Docking studies of the FRBI‐8 with reported FSH–FSHR hormone binding (FSHRHB) domain complex using zdock algorithm revealed that the FRBI‐8 binds to FSHβL2–FSHRHB binding interface which is otherwise known to be crucial for activation of signal transduction cascade. FRBI‐8 analogs were designed by replacing the acidic amino acid residues at positions 2, 5 and 6 with Ala, individually. Docking studies revealed that D6A mutant (FRBI‐8D6A) had a higher binding affinity than the native FRBI‐8. In vitro radioreceptor assay with FRBI‐8D6A showed 50% lower IC50 compared with the FRBI‐8, confirming the in silico observations. Thus, the study reveals that both FRBI‐8 and FRBI‐8D6A interfered with the binding of FSH to its receptor. 相似文献
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《The Journal of pharmacy and pharmacology》2018,70(10):1340-1348