A development of chimeric VEGFR2 TK inhibitor based on two ligand conformers from PDB: 1Y6A complex – Medicinal chemistry consequences of a TKs analysis

Lintnerová, Lucia; García-Caballero, Melissa; Gregáň, Fridrich; Melicherčík, Milan; Quesada, Ana R.; Dobiáš, Juraj; Lác, Ján; Sališová, Marta; Boháč, Andrej

doi:10.1016/j.ejmech.2013.11.023

Cited by 38 publications

(22 citation statements)

References 18 publications

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“…The mechanism explaining the formation of XXI was proposed (Scheme 8). We were able to prepare a number of novel VEGFR2 inhibitors using this method (e.g., 3 bispyridyl, para-OH and para-OMe derivatives of AAZ) [32].…”

Section: Resultsmentioning

confidence: 99%

Selected Methodologies Convenient for the Synthesis of N,5‐Diaryloxazole‐2‐amine Pharmacophore

Lintnerová

Kovacikova

Hanquet

et al. 2014

Journal of Heterocyclic Chem

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Section: Resultsmentioning

confidence: 99%

Selected Methodologies Convenient for the Synthesis of N,5‐Diaryloxazole‐2‐amine Pharmacophore

Lintnerová

Kovacikova

Hanquet

et al. 2014

Journal of Heterocyclic Chem

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“…Therefore, for our docking experiments we selected the kinase variants of VEGFR2 from PDB complexes 1Y6A and 1Y6B possessing structurally the most relative oxazole ligands (AAZ and AAX, resp.). These ligands represent Type I, ATP competitive VEGFR2 inhibitors that bind to an exceptional inactive VEGFR2 tyrosine kinase possessing an opened activation loop as was discovered by us recently [14]. Because the structure similarity between AAZ (AAX) and proposed triazoles (e.g.…”

Section: In Silico Predictionsmentioning

confidence: 99%

“…Ligand AAZ was prepared in five steps in a low overall 10% yield mostly due to the problematic oxazole-2-amine fragment formation [12]. Low yields of oxazole-2-amine formation (1e58 %) have been also described [13,14]. Moreover AAZ contains N-aryloxazol-2-amine part that uses to liberate from connection with oxazole by influence of nucleophilic reagent (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover proposed positions of the above triazole inhibitors in VEGFR2 ATP active site is similar to the poses of ligands from PDB complexes 2P2I (IC 50 : 38 nM), and 3EFL (IC 50 : 3 nM). (not shown) Both VEGFR2 kinase conformers (PDB: 2P2I and 3EFL) used in docking experiments are VEGFR2 inactive (DFG-out) kinases originally accommodating Type II inhibitor [14].…”

Section: Introductionmentioning

confidence: 99%

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Ynamide Click chemistry in development of triazole VEGFR2 TK modulators

Vojtíčková

Dobiáš

Hanquet

et al. 2015

European Journal of Medicinal Chemistry

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Keywords:Oxazole/1,2,3-triazole isosteric replacement Ynamide CuACC Click chemistry VEGFR2 tyrosine kinase inhibition Cytotoxic activity in Huh-7 and Mahlavu hepatocellular carcinoma cell lines PI3K/Akt pathway a b s t r a c t Structure novelty, chemical stability and synthetic feasibility attracted us to design 1,2,3-triazole compounds as potential inhibitors of VEGFR2 tyrosine kinase. Novel triazoles T1eT7 were proposed by oxazole (AAZ from PDB: 1Y6A)/1,2,3-triazole isosteric replacement, molecular modelling and docking. In order to enable synthesis of T1eT7 we developed a methodology for preparation of ynamide 22. Compound 22 was used for all Click chemistry reactions leading to triazoles T1eT3 and T6eT7. Among the obtained products, T1, T3 and T7 specifically bind VEGFR2 TK and modulate its activity by concentration dependent manner. Moreover predicted binding poses of T1eT7 in VEGFR2 TK were similar to the one known for the oxazole inhibitor AAZ (PDB: 1Y6A). Unfortunately the VEGFR2 inhibition by triazoles e.g. T3 and T7 is lower than that determined for their oxazole bioisosters T3-ox and AAZ, resp. Different electronic properties of 1,2,3-triazole/oxazole heterocyclic rings were proposed to be the main reason for the diminished affinity of T1eT3, T6 and T7 to an oxazole AAZ inhibitor binding site in VEGFR2 TK (PDB: 1Y6A or 1Y6B). Moreover T1eT3 and T6 were screened on cytotoxic activity against two human hepatocellular carcinoma cell lines. Selective cytotoxic activity of T2 against aggressive Mahlavu cells has been discovered indicating possible affinity of T2 to Mahlavu constitutionally active PI3K/Akt pathway.

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“…The phenyl moiety occupies the hydrophobic back pocket nearby the ATP binding cleft of the receptor. This hydrophobic pocket is essential for the binding of groups of the tyrosine kinase inhibitors …”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, in silico and antiproliferative evaluation of novel pyrazole derivatives as VEGFR‐2 inhibitors

Ravula

Vamaraju

Paturi

et al. 2017

Archiv der Pharmazie

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As the blockade of the VEGFR-2 signaling pathway is a viable approach in cancer therapy, the present study focuses on a series of pyrazole based VEGFR-2 inhibitors that were designed on the basis of the hybridization approach, supported by docking and in silico computational studies. The designed compounds were synthesized through facile synthetic methods and the structures were K E Y W O R D Santiproliferative activity, molecular modeling, synthesis, VEGFR-2

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A development of chimeric VEGFR2 TK inhibitor based on two ligand conformers from PDB: 1Y6A complex – Medicinal chemistry consequences of a TKs analysis

Cited by 38 publications

References 18 publications

Selected Methodologies Convenient for the Synthesis of N,5‐Diaryloxazole‐2‐amine Pharmacophore

Selected Methodologies Convenient for the Synthesis of N,5‐Diaryloxazole‐2‐amine Pharmacophore

Ynamide Click chemistry in development of triazole VEGFR2 TK modulators

Design, synthesis, in silico and antiproliferative evaluation of novel pyrazole derivatives as VEGFR‐2 inhibitors

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