Synthesis and Biological Evaluations of 3-Substituted Indolin-2-ones: A Novel Class of Tyrosine Kinase Inhibitors That Exhibit Selectivity toward Particular Receptor Tyrosine Kinases (original) (raw)
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Biological & Pharmaceutical Bulletin, 2007
Human protein kinase CK2 is an ubiquitous serine/threonine kinase that is typically found in tetrameric complexes consisting of two catalytic (a a and/or a a) and two regulatory b b subunits. Although there is growing evidence that besides the participation of CK2 in a complex series of cellular functions, this protein kinase is involved in cell viability, cell proliferation, and neoplastic transformation. In the present study, a series of 3-(substituted-benzylidene)-1,3-dihydro-indolin-2-thione derivatives and the corresponding indolin-2-one congeners were tested for their inhibition of human recombinant protein kinase CK2 in vitro. The efficacy of these compounds was compared with their inhibitory results of p60 c-Src tyrosine kinase. It was found that 3-(substituted-benzylidene)-1,3-dihydro-indolin-2-thione derivatives are more effective than indolin-2-one congeners for the inhibition of CK2 and p60 c-Src tyrosine kinase.
Il Farmaco, 2005
A series of 3-(substituted-benzylidene)-1, 3-dihydro-indolin-2-thione derivatives were synthesized as modified congeners of 3-(substitutedbenzylidene)-1, 3-dihydro-indolin-2-one series. All the synthesized compounds were examined for their in vitro anti-tyrosine kinase activity against p60 c-Src . The activity results revealed that compounds (Z)-3-(4′-Dimethylamino-benzylidene)-1, 3-dihydro-indolin-2-thione (12) (E)-3-(2′, 6′-Dichloro-benzylidene)-1, 3-dihydro-indolin-2-thione (13) and (E)-3-(3′-Hydroxy-4′-methoxy-benzylidene)-1, 3-dihydro-indolin-2thione (19) exhibited anti-tyrosine kinase activity with IC 50 value of 21.91, 21.20 and 30.92 µM, respectively. These results are comparable to PP1 [1-tert-Butyl-3-p-tolyl-1H-pyrazolo[3, 4-d]pyrimidine-4-yl-amine] (IC 50 = 0.17 µM), which is reported as a potent and selective p60 c-Src tyrosine kinase inhibitor. Some thio congeners are found to be more potent than oxo derivatives; however, no significant correlation was observed between the activity profiles of these two series. Docking program was used to investigate the docking mode of each compound at the active site. Among all of the compounds, only (Z)-3-(2′-Chloro-benzylidene)-1, 3-dihydro-indolin-2-one (8) and (E)-3-(3′-Nitrobenzylidene)-1, 3-dihydro-indolin-2-thione (16) were docked at the active site where the PP1 was embedded.
Journal of Medicinal Chemistry, 1994
A series of indole-substituted 2,2'-dithiobis(l-methyl-N-phenyl-1H-indole-3-carboxamides) were prepared and evaluated for their ability to inhibit the tyrosine kinase activity of both the epidermal growth factor receptor (EGFR) and the nonreceptor ppG0V-B" tyrosine kinase. The compounds were synthesized by conversion of appropriate 1-methyloxindoles to 1-methyl-Zindolinethiones with P2s5 followed by subsequent reaction with NaH and phenyl isocyanate and oxidative dimerization of the resulting 2,3-dihydro-N-phenyl-2-thioxo-W-indole-3-carboxamides. The parent compound and many of the substituted analogues were moderately potent inhibitors of both kinase enzymes, but no clear relationships were seen between substitution on the indole ring and inhibitory activity. While 4-substituted compounds were generally inactive, 5-substituted derivatives with electron-withdrawing groups showed inhibitory activity. However, none of the substituted compounds showed significantly better activity than the unsubstituted parent compound. There was generally a good correlation between activity against the EGFR and pp60v-src kinases, but several compounds did show some specificity (>20-fold) of inhibition; 5 4 1 and 5-Br derivatives preferentially inhibited pp6Ovem, while the 5-CF3 compound preferentially inhibited EGFR. Selected compounds from the series were found to inhibit the growth of Swiss 3T3 fibroblasts with IC@ in the range 2-25 p M , the most active being 4-substituted derivatives. The compounds inhibited bFGF-mediated protein tyrosine phosphorylation in intact cells more effectively than EGFR-or PDGF-mediated phosphorylation. * Parke-Davis Pharmaceutical Research.
Structure-based drug design and AutoDock study of potential protein tyrosine kinase inhibitors
Bioinformation, 2011
Different classes of compounds were investigated for their binding affinities into different protein tyrosine kinases (PTKs) employing a novel flexible ligand docking approach by using AutoDock 3.05 and 4. These compounds include many flavin analogs, which were developed in our group with varying degrees of cytotoxic activity (comparable or moderately superior to cisplatin and ara-c), and database selected analogs. They were docked onto twelve different families of PTKs retrieved from the Protein Data Bank. These proteins are representatives of plausible models of interactions with chemotherapeutic agents. A comparative study of the intact co-crystallized ligands of various types of PTKs was carried out. Results revealed that the new class of 5-deazapteridine and steroid hybrid compounds VIa,b, and d, and the vertical-type bispyridodipyrimidine with n-hexyl chain junction between its N-10 and N-10 atoms Xa, exhibited non-selective PTK binding capacities, with the lowest Gb. On the other hand, 2-amino benzoic acid analog IIa, phenoxypyrido [3, 4-d]pyrimidine derivative IVc, tyrosine containing tripeptide Vd, and the one from Sumisho data base 831 are proposed to have selective PTK binding affinities to certain classes of tyrosine kinases, namely, HGFR (c-met), ZAP-70, insulin receptor kinase, EGFR, respectively. All These compounds of highest affinities were docked within the binding sites of PTKs with reasonable RMSD and 1-5 hydrogen bonds.
African Journal of Traditional, Complementary and Alternative Medicines, 2012
Traditional medicines have become the most productive source of leads for drugs development, particularly as anti-cancer agents. Various screening approaches are being applied. Sorafenib, a multikinase inhibitor, is used to treat primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer. A small library of compounds analogous to sorafenib were designed and screened for the treatment of liver cancer. Multiple members of the family in an assay panel of tyrosine kinase family and serine/threonine-protein kinase family, including VEGFR, Abl, Aurora A, p 38, Lck, Src, PDGFR, Flt3, c-RAF, c-KIT, MEK(MAPKK) were selected to test these compounds. Analysis of the selectivity patterns for these compounds shows specificity for many kinase families. IC 50 were measured for the selected compounds.
Asian Journal of Biomedical and Pharmaceutical Sciences, 2014
Protein tyrosine kinases (PTKs) are important components for signal pathways that control cell proliferation, differentiation and various regulatory mechanisms. Selective inhibition of the PTKs is now recognized as an attractive strategy for the development of new cancer therapeutics. Indolinone derivatives are already proved as potential PTK inhibitors of Fibroblast Growth Factor Receptor (FGFR) and anti cancer agent. In the present work, a set of indolinone derivatives are considered for chemometric designing for anti-cancer agents using ligand-based 3D QSAR and pharmacophore modelling studies. The 3D-QSAR models permit an understanding of steric, electrostatic, and hydrophobic along with HB acceptor and donor requirements for ligand interactions at the active site. Pharmacophore is the molecular framework that carries the essential features that can visualize the potential interaction between the ligand and the receptor and it is based on the kind of interactions observed in molecular recognition. In the present study, molecular field and similarity analyses (CoMFA: R 2 =0.997, Q 2 =0.714, se=0.037, R 2 pred=0.602, sp=0.351; CoMSIA: R 2 =0.999, Q 2 =0.747, se=0.016, R 2 pred=0.712, sp =0.541) explained that both steric and electrostatic are crucial for inhibitory activity. Additionally, HB acceptor and donor are obtained as important for HB bonding interactions. The pharmacophore modelling study (R 2 = 0.924, Q 2 =0.752, se=0.047, R 2 pred=0.771, s p =0.421) revealed the importance of HB acceptor and donor for the binding interaction at the active site cavity along with ring aromatic feature is found to be prime factor for inhibitory activity of the molecules. The study explained that rings 'C' and 'D' along with carbon chain between them are found to be essential for inhibitory activity. The amine and oxo group present in the ring 'C' also found critical for bonding interactions in the active site cavity of tyrosin kinase.
Cheminfomatic-based Drug Discovery of Human Tyrosine Kinase Inhibitors
Current Topics in Medicinal Chemistry, 2016
Receptor Tyrosine Kinases (RTKs) are essential components for regulating cell-cell signaling and communication events in cell growth, proliferation, differentiation, survival and metabolism. Deregulation of RTKs and their associated signaling pathways can lead to a wide variety of human diseases such as immunodeficiency, diabetes, arterosclerosis, psoriasis and cancer. Thus RTKs have become one of the most important drug targets families in recent decade. Pharmaceutical companies have dedicated their research efforts towards the discovery of small-molecule inhibitors of RTKs, many of which had been approved by the U.S. Food and Drug Administration (US FDA) or are currently in clinical trials. The great successes in the development of smallmolecule inhibitors of RTKs are largely attributed to the use of modern cheminformatic approaches to identifying lead scaffolds. Those include the quantitative structure-activity relationship (QSAR) modeling, as well as the structure-, and ligand-based pharmacophore modeling techniques in this case. Herein we inspected the literature thoroughly in an effort to conduct a comparative analysis of major findings regarding the essential structure-activity relationships (SARs)/pharmacophore features of known active RTK inhibitors, most of which were collected from cheminformatic modeling approaches.
Journal of Medicinal Chemistry, 2009
The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATPcompetitive inhibitors of VEGFR-2, FGFR-1, and PDGFR with IC 50 values <0.1 µM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.
Identification of a Novel Series of Potent TrkA Receptor Tyrosine Kinase Inhibitors
International Journal of Medicinal Chemistry, 2012
A novel series of N-(3-(6-substituted-aminopyridin-3-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting TrkA receptor tyrosine kinase was identified. SAR study of the series allowed us to design and synthesize compounds possessing inhibitory activity of TrkA kinase enzyme in the low nanomolar range with low residual activity against c-Met and with no significant activity against VEGFR2.