Discovery of a novel and potent series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases

Claridge, Stephen; Raeppel, Franck; Granger, Marie-Claude; Bernstein, Naomy; Saavedra, Oscar M.; Zhan, Lijie; Llewellyn, David B.; Wahhab, Amal; Déziel, Robert; Rahil, Jubrail; Beaulieu, Normand; Nguyen, Hannah; Dupont, Isabelle; Barsalou, Annie; Beaulieu, Carole; Chute, Ian C.; Gravel, Serge; Robert, Mathieu; Lefèbvre, Sylvain; Dubay, Marja; Pascal, Roussen; Gillespie, Jeff; Jin, Zhiyun; Wang, Jinru; Besterman, Jeffrey M.; MacLeod, A. Robert; Vaisburg, A. F.

doi:10.1016/j.bmcl.2008.04.009

Cited by 58 publications

(30 citation statements)

References 23 publications

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“…[12][13][14][15] Magnetoliposomes are specially promising as nanocarriers for potential antitumor drugs. Thienopyridine derivatives have been reported as possessing antiangiogenic, [16][17][18][19][20][21] antitumor, [21][22][23][24][25][26][27][28][29] or both activities. 30 Among the potential antitumor di(hetero)arylamines in the thieno [3,2-b]pyridine series, prepared earlier by some of us, the ones with an o-methoxy or m-methoxy groups relative to the NH (compounds 1 and 2, Fig.…”

Section: Introductionmentioning

confidence: 99%

Magnetoliposomes as carriers for promising antitumor thieno[3,2-b]pyridin-7-arylamines: photophysical and biological studies

et al. 2017

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Magnetoliposomes containing superparamagnetic manganese ferrite nanoparticles were tested as nanocarriers for two new promising antitumor drugs, a N-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-amine (1) and a N-(2-methoxy-phenyl)thieno[3,2-b]pyridin-7-amine (2). The fluorescence emission of both compounds was studied in different polar and non-polar media, evidencing a strong intramolecular charge transfer character of the excited state of both compounds. These in vitro potent antitumor thienopyridine derivatives were successfully incorporated in both aqueous and solid magnetoliposomes, with encapsulation efficiencies higher than 75%. The magnetic properties of magnetoliposomes containing manganese ferrite nanoparticles were measured for the first time, proving a superparamagnetic behaviour. Growth inhibition assays on several human tumor cell lines showed very low GI 50 values for drug-loaded aqueous magnetoliposomes, comparing in most cell lines with the ones previously obtained using the neat compounds. These results are important for future drug delivery applications using magnetoliposomes in oncology, through a dual therapeutic approach (simultaneous chemotherapy and magnetic hyperthermia).

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Section: Introductionmentioning

confidence: 99%

Magnetoliposomes as carriers for promising antitumor thieno[3,2-b]pyridin-7-arylamines: photophysical and biological studies

et al. 2017

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“…And the structureactivity relationships of the c-Met type II inhibitors to c-Met were systematically investigated based on the computationally determined binding modes. The large number of c-Met inhibitors with reported activities [9,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] as well as the six c-Met crystal structures (pdb code: 2WGJ, 2WKM, 3ZXZ, 3ZZE, 3LQ8 and 3U6I) [11,12,14,32] in complex with some of these inhibitors gave rise to the possibility to test our methods.…”

Section: Introductionmentioning

confidence: 99%

Development of efficient docking strategies and structure-activity relationship study of the c-Met type II inhibitors

Kaas

et al. 2017

Journal of Molecular Graphics and Modelling

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Graphical AbstractTOC c-Met is a tyrosine kinase and an important therapeutic target for anticancer drugs. In present study, we systematically investigated the influence of a range of parameters on the correlation between experimental and calculated binding energies of type II c-Met inhibitors. Results from this study will form the basis for establishing an efficient computational docking approach for c-Met type II inhibitors design. Highlights• Testing a set of influences to the ranking ability of the docking program in MOE.• Structure-activity relationship study of c-Met type II inhibitors.• Establishing an efficient computational docking approach for c-Met type II inhibitors design.ABSTRACT： c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In the present study, we systematically investigated the influence of a range of parameters on the correlation between experimental and calculated binding free energies of type II c-Met inhibitors. We especially focused on evaluating the impact of different force fields, binding energy calculation methods, docking protocols, conformation sampling strategies, and conformations of the binding site captured in several crystallographic structures. Our results suggest that the force fields, the protein flexibility, and the selected conformation of the binding site substantially influence the correlation coefficient, while the sampling strategies and ensemble docking only mildly affect the prediction accuracy. Structure-activity relationship study suggests that the structural determinants to the high binding affinity of the type II inhibitors originate from its overall linear shape, hydrophobicity, and two conserved hydrogen bonds. Results from this study will form the basis for establishing an efficient computational docking approach for c-Met type II inhibitors design.

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“…The residue was purified by column chromatography giving compound 12 (324 mg, 65%) as a white solid. (13). To the solution of compound 12 (239 mg 1mmol) and 4-methoxybenzylamine (192 mg, 1.4 mmol) in DMF (8 mL) was added K 2 CO 3 (152 mg, 1.1 mmol).…”

Section: General Informationmentioning

confidence: 99%

“…Chemical shifts of the 1 H-NMR spectra are expressed in ppm relative to the solvent residual signal 7.26 in CDCl 3 or to tetramethylsilane (δ = 0.00). Chemical shifts of the 13 C-NMR spectra are expressed in ppm relative to the solvent signal 77.00 in CDCl 3 or to tetramethylsilane (δ = 0.00) unless otherwise noted. Electrospray (ESI) mass spectra were recorded on a Global Q-TOF mass spectrometer (Waters, Wilford, MA, USA).…”

Section: General Informationmentioning

confidence: 99%

“…Generally, structural optimization based on compound 1 mainly focused on moiety D and B. Replacement of the 6,7-dimethoxyquinoline moiety by various N-containing heterocycles, such as substituted quinoline [12], thienopyridine [13][14][15], pyrrolopyridine [16], aminopyridine [17], thienopyrimidine [18], furopyrimidine [18], imidazopyridine [19] or imidazopyridazine [19], has been investigated. The bridge moiety B connecting moiety A and C was designed as linear [20][21][22] or cyclic [14,15,[23][24][25][26], bearing at least one amide bond with 5-atoms in the main chain [22,24] (i.e., six chemical bonds distance between moiety A and C, Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Novel c-Met Inhibitors Bearing a 3-Carboxyl Piperidin-2-one Scaffold

Zhang

Shi

et al. 2014

Molecules

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A series of compounds containing a novel 3-carboxypiperidin-2-one scaffold based on the lead structure BMS-777607 were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against MKN45 cancer cell lines. The results indicated that five compounds exhibited significant inhibitory effect on c-Met with IC 50 values of 8.6−81 nM and four compounds showed potent inhibitory activity against MKN45 cell proliferation, with IC 50 s ranging from 0.57−16 μM.

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Discovery of a novel and potent series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases

Cited by 58 publications

References 23 publications

Magnetoliposomes as carriers for promising antitumor thieno[3,2-b]pyridin-7-arylamines: photophysical and biological studies

Magnetoliposomes as carriers for promising antitumor thieno[3,2-b]pyridin-7-arylamines: photophysical and biological studies

Development of efficient docking strategies and structure-activity relationship study of the c-Met type II inhibitors

Discovery of Novel c-Met Inhibitors Bearing a 3-Carboxyl Piperidin-2-one Scaffold

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