- Novel Human Aminopeptidase N Inhibitors: Discovery and Optimization of Subsite Binding Interactions
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Aminopeptidase N (APN/CD13) is a zinc-dependent M1 aminopeptidase that contributes to cancer progression by promoting angiogenesis, metastasis, and tumor invasion. We have previously identified hydroxamic acid-containing analogues that are potent inhibitors of the APN homologue from the malarial parasite Plasmodium falciparum M1 aminopeptidase (PfA-M1). Herein, we describe the rationale that underpins the repurposing of PfA-M1 inhibitors as novel APN inhibitors. A series of novel hydroxamic acid analogues were developed using a structure-based design approach and evaluated their inhibition activities against APN. N-(2-(Hydroxyamino)-2-oxo-1-(3′,4′,5′-trifluoro-[1,1′-biphenyl]-4-yl)ethyl)-4-(methylsulfonamido)benzamide (6ad) proved to be an extremely potent inhibitor of APN activity in vitro, selective against other zinc-dependent enzymes such as matrix metalloproteases, and possessed limited cytotoxicity against Ad293 cells and favorable physicochemical and metabolic stability properties. The combined results indicate that compound 6ad may be a useful lead for the development of anticancer agents.
- Lee, Jisook,Vinh, Natalie B.,Drinkwater, Nyssa,Yang, Wei,Kannan Sivaraman, Komagal,Schembri, Luke S.,Gazdik, Michelle,Grin, Peter M.,Butler, Georgina S.,Overall, Christopher M.,Charman, Susan A.,McGowan, Sheena,Scammells, Peter J.
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supporting information
p. 7185 - 7209
(2019/08/28)
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- Synthesis, anti-lung cancer activity and molecular docking study of 3-methylene-2-oxoindoline-5-carboxamide derivatives
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A series of 3-methylene-2-oxoindoline-5-carboxamide derivatives were synthesized in appreciable yield by using 4-aminobenzoic acid as a starting material. The preliminary biological test results showed that most compounds displayed potent inhibitory activity against proliferation of human lung adenocarcinoma epithelial cell line (A549) in MTT assay. Compound 6l displayed the highest potency (IC50 = 3.0 μM). The western blot analysis demonstrated a correlation between anti-proliferative activity of active compounds and blockade of the phosphorylation of extracellular signal-regulated kinases (ERK1/2). The docking study also provides new insights into further optimization of 3-methylene-2-oxoindoline-5-carboxamide derivatives for the discovery of more potent RAF/MEK/ERK pathway regulators as anti-lung cancer agents.
- Ai, Juntao,Lv, Meng,Li, Xiaohui,Chen, Zhuo,Hu, Gaoyun,Li, Qianbin
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p. 161 - 170
(2018/04/17)
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- Design, synthesis, structure-activity relationships study and X-ray crystallography of 3-substituted-indolin-2-one-5-carboxamide derivatives as PAK4 inhibitors
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We have previously described the identification of indolin-2-one-5-carboxamides as potent PAK4 inhibitors. This study expands the structure-activity relationships on our original series by presenting several modifications in the lead compounds, 2 and 3. A series of novel derivatives was designed, synthesized, and evaluated in biochemical and cellular assay. Most of this series displayed nanomolar biochemical activity and potent antiproliferative activity against A549 and HCT116 cells. The representative compound 10a exhibited excellent enzyme inhibition (PAK4 IC50 = 25 nM) and cellular potency (A549 IC50 = 0.58 μM, HCT116 IC50 = 0.095 μM). An X-ray structure of compound 10a bound to PAK4 was obtained. Crystallographic analysis confirmed predictions from molecular modeling and helped refine SAR results. In addition, Compound 10a displayed focused multi-targeted kinase inhibition, good calculated drug-likeness properties. Further profiling of compound 10a revealed it showed weak inhibitory activity against various isoforms of human cytochrome P450.
- Guo, Jing,Zhao, Fan,Yin, Wenbo,Zhu, Mingyue,Hao, Chenzhou,Pang, Yu,Wu, Tianxiao,Wang, Jian,Zhao, Dongmei,Li, Haitao,Cheng, Maosheng
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p. 197 - 209
(2018/06/12)
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- SMYD INHIBITORS
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The present disclosure provides carboxamides and sulfonamides having Formula (I): and the pharmaceutically acceptable salts and solvates thereof, wherein A, Y, B, X, and Z are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula (I) to treat a disorder responsive to the blockade of SMYD proteins such as SMYD3 or SMYD2. Compounds of the present disclosure are especially useful for treating cancer.
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Paragraph 0952; 0955-0957
(2017/07/18)
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- Discovery of indolin-2-one derivatives as potent PAK4 inhibitors: Structure-activity relationship analysis, biological evaluation and molecular docking study
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Utilizing a pharmacophore hybridization approach, a novel series of substituted indolin-2-one derivatives were designed, synthesized and evaluated for their in vitro biological activities against p21-activated kinase 4. Compounds 11b, 12d and 12g exhibited the most potent inhibitory activity against PAK4 (IC50?=?22?nM, 16?nM and 27?nM, respectively). Among them, compound 12g showed the highest antiproliferative activity against A549 cells (IC50?=?0.83?μM). Apoptosis analysis in A549 cells suggested that compound 12g delayed cell cycle progression by arresting cells in the G2/M phase of the cell cycle, retarding cell growth. Further investigation demonstrated that compound 12g strongly inhibited migration and invasion of A549 cells. Western blot analysis indicated that compound 12g potently inhibited the PAK4/LIMK1/cofilin signalling pathways. Finally, the binding mode between compound 12g with PAK4 was proposed by molecular docking. A preliminary ADME profile of the compound 12g was also drawn on the basis of QikProp predictions.
- Guo, Jing,Zhu, Mingyue,Wu, Tianxiao,Hao, Chenzhou,Wang, Kai,Yan, Zizheng,Huang, Wanxu,Wang, Jian,Zhao, Dongmei,Cheng, Maosheng
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p. 3500 - 3511
(2017/05/29)
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- SELECTIVE HDAC3 INHIBITORS
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Provided herein are HDAC3 inhibitors, as well as methods of treatment comprising administering these compounds to a subject in need thereof.
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Page/Page column 30
(2014/08/19)
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- COMPOSITIONS AND METHODS FOR TREATMENT OF NEURODEGENERATIVE DISEASE
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Compounds, compositions, kits and methods for treating conditions related to neurodegeneration or ocular disease, are disclosed.
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Page/Page column 29-30
(2011/10/13)
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- 5-Substituted pyrido[2,3-d]pyrimidine, an inhibitor against three receptor tyrosine kinases
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NP506, the 3-{2,4-dimethyl-5-[2-oxo-5-(N′-phenylhydrazinocarbonyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrol-3-yl}-propionic acid, was designed as FGF receptor 1 inhibitor by computational study and found to be more active against endothelial proliferation of HUVEC after the rhFGF-2 stimulation than SU6668 with minimum effective dose of 10 μM. NP506 inhibited the tyrosine phosphorylation in FGF, VEGF, and PDGF receptors and the activation of extracellular signal-regulated kinase (ERK), c-Jun-N-terminal-kinase (JNK) and AKT after the rhFGF-2 stimulation. The introduction of the phenyl hydrazide motif to the position 5 of the pyrido[2,3-d]pyrimidine scaffold led to the inhibitory effect in two signaling pathways: inhibition of AKT activation in the phosphatidyl inositol 3′-kinase (PI13K)/AKT signaling pathway and the inhibition of ERK and JNK activation in MAPK pathway.
- Kammasud, Naparat,Boonyarat, Chantana,Sanphanya, Kingkan,Utsintong, Maleeruk,Tsunoda, Satoshi,Sakurai, Hiroaki,Saiki, Ikuo,André, Isabelle,Grierson, David S.,Vajragupta, Opa
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scheme or table
p. 745 - 750
(2009/09/25)
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- NOVEL HYDROXYINDOLE DERIVATIVE
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A compound or a pharmaceutically acceptable salt thereof of the present invention is represented by the following general formula (I): [wherein, R1 to R8 may have a hydrogen atom, a halogen atom, a hydroxy group, a C1-C6 alkyl group,
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Page/Page column 19-20
(2009/12/24)
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- 3-(cycloalkanoheteroarylidenyl)-2-indolinone protein tyrosine kinase inhibitors
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The present invention relates to novel 3-(cycloalkano-heteroarylidenyl)-2-indolinone compounds and physiologically acceptable salts and prodrugs thereof which are expected to modulate the activity of protein tyrosine kinases and therefore to be useful in the prevention and treatment of protein tyrosine kinase related cellular disorders such as cancer.
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Page column 24
(2010/02/05)
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- Methods of modulating protein tyrosine kinase function with substituted indolinone compounds
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The invention relates to certain indolinone compounds, their method of synthesis, and a combinatorial library consisting of the indolinone compounds. The invention also relates to methods of modulating the function of protein kinases using indolinone compounds and methods of treating diseases by modulating the function of protein kinases and related signal transduction pathways.
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- Pyrrole substituted 2-indolinone protein kinase inhibitors
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The present invention relates to novel pyrrole substituted 2-indolinone compounds and physiologically acceptable salts and prodrugs thereof which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.
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- 3-heteroarylidene-2-indolinone protein kinase inhibitors
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The present invention relates to novel 3-heteroarylidene-2-indolinone compounds and physiologically acceptable salts thereof which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.
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- Indolinone combinatorial libraries and related products and methods for the treatment of disease
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The present invention relates to organic molecules capable of modulating, regulating and/or inhibiting protein kinase signal transduction. Such compounds are useful for the treatment of diseases related to unregulated protein kinase signal transduction, including cell proliferative diseases such as cancer, atherosclerosis, arthritis and restenosis and metabolic diseases such as diabetes. The present invention features indolinone compounds that potently inhibit protein kinases and related products and methods. Inhibitors specific to the FLK protein kinase can be obtained by adding chemical substituents to the 3-[(indole-3-yl)methylene]-2-indolinone, in particular at the 1' position of the indole ring. Indolinone compounds that specifically inhibit the FLK and platelet derived growth factor protein kinases can harbor a tetrahydroindole or cyclopentano-b-pyrrol moiety. Indolinone compounds that are modified with substituents, particularly at the 5 position of the oxindole ring, can effectively activate protein kinases. This invention also features novel hydrosoluble indolinone compounds that are tyrosine kinase inhibitors and related products and methods.
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- 3-(cycloalkanoheteroarylidenyl)-2- indolinone protein tyrosine kinase inhibitors
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The present invention relates to novel 3-(cycloalkanoheteroarylidenyl)-2-indolinone compounds and physiologically acceptable salts and prodrugs thereof which are expected to modulate the activity of protein tyrosine kinases and therefore to be useful in the prevention and treatment of protein tyrosine kinase related cellular disorders such as cancer.
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- Design, synthesis, and evaluations of substituted 3-[(3- or 4- carboxyethylpyrrol-2-yl)methylidenyl]indolin-2-ones as inhibitors of VEGF, FGF, and PDGF receptor tyrosine kinases
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Receptor tyrosine kinases (RTKs) have been implicated as therapeutic targets for the treatment of human diseases including cancers, inflammatory diseases, cardiovascular diseases including arterial restenosis, and fibrotic diseases of the lung, liver, and kidney. Three classes of 3-substituted indolin-2-ones containing propionic acid functionality attached to the pyrrole ring at the C-3 position of the core have been identified as catalytic inhibitors of the vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) RTKs. Some of the compounds were found to inhibit the tyrosine kinase activity associated with isolated vascular endothelial growth factor receptor 2 (VEGF-R2) [fetal liver tyrosine kinase 1 (Flk-1)/kinase insert domain- containing receptor (KDR)], fibroblast growth factor receptor (FGF-R), and platelet-derived growth factor receptor (PDGF-R) tyrosine kinase with IC50 values at nanomolar level. Thus, compound 1 showed inhibition against VEGF-R2 (Flk-1/KDR) and FGF-R1 tyrosine kinase activity with IC50 values of 20 and 30 nM, respectively, while compound 16f inhibited the PDGF-R tyrosine kinase activity with IC50 value of 10 nM. Structural models and structure-activity relationship analysis of these compounds for the target receptors are discussed. The cellular activities of these compounds were profiled using cellular proliferation assays as measured by bromodeoxyuridine (BrdU) incorporation. Specific and potent inhibition of cell growth was observed for some of these compounds. These data provide evidence that these compounds can be used to inhibit the function of these target receptors.
- Sun, Li,Tran, Ngoc,Liang, Congxin,Tang, Flora,Rice, Audie,Schreck, Randall,Waltz, Kara,Shawver, Laura K.,McMahon, Gerald,Tang, Cho
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p. 5120 - 5130
(2007/10/03)
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- Substituted piperazinyl oxindol compounds and cardiotonic compositions containing the same
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An oxindol compound of the formula (I) STR1 wherein A represents a lower alkylene group; R represents a hydrogen atom, a lower alkyl group, a phenyl-lower alkyl group, a phenoxy-lower alkyl group, a benzoyl-lower alkyl group, a lower alkoxycarbonyl group,
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