Rational Design, Synthesis, and Biological Evaluation of 7-Azaindole Derivatives as Potent Focused Multi-Targeted Kinase Inhibitors

Dayde, Bénédicte; Fauvel, Bénédicte; Singer, Mathilde; Feneyrolles, Clémence; Bestgen, Benoît; Gassiot, Fanny; Spenlinhauer, Aurélia; Warnault, Pierre; Hijfte, Nathalie Van; Borjini, Nozha; Chevé, Gwénaël; Yasri, Abdelaziz

doi:10.1021/acs.jmedchem.6b00087

Cited by 48 publications

(19 citation statements)

References 19 publications

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“…For a good model, structure should retain an ERRAT score >80.00, against which the model in this study obtained an ERRAT score of 89.859 55. Verify 3D graph indicates that 100.00% of residues of this model had an averaged 3D-1D score of 0.2, which is good 59. Along with the QMEAN analysis, the protein model in our interest resulted in a Z-score of −1.33, and the total score was 0.636.…”

Section: Resultsmentioning

confidence: 64%

In silico-based vaccine design against Ebola virus glycoprotein

Dash¹,

Das²,

Junaid³

et al. 2017

AABC

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Ebola virus (EBOV) is one of the lethal viruses, causing more than 24 epidemic outbreaks to date. Despite having available molecular knowledge of this virus, no definite vaccine or other remedial agents have been developed yet for the management and avoidance of EBOV infections in humans. Disclosing this, the present study described an epitope-based peptide vaccine against EBOV, using a combination of B-cell and T-cell epitope predictions, followed by molecular docking and molecular dynamics simulation approach. Here, protein sequences of all glycoproteins of EBOV were collected and examined via in silico methods to determine the most immunogenic protein. From the identified antigenic protein, the peptide region ranging from 186 to 220 and the sequence HKEGAFFLY from the positions of 154–162 were considered the most potential B-cell and T-cell epitopes, correspondingly. Moreover, this peptide (HKEGAFFLY) interacted with HLA-A*32:15 with the highest binding energy and stability, and also a good conservancy of 83.85% with maximum population coverage. The results imply that the designed epitopes could manifest vigorous enduring defensive immunity against EBOV.

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Section: Resultsmentioning

confidence: 64%

In silico-based vaccine design against Ebola virus glycoprotein

Dash¹,

Das²,

Junaid³

et al. 2017

AABC

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“…The three targeted RTKs are involved in both angiogenesis and tumorigenesis [ 21 ]. With the aim of developing anti-angiogenic and anticancer agents, we firstly evaluated the title compounds for their inhibitory effect and selectivity among various RTKs.…”

Section: Resultsmentioning

confidence: 99%

Discovery and evaluation of triple inhibitors of VEGFR-2, TIE-2 and EphB4 as anti-angiogenic and anti-cancer agents

Zhang

Shan

et al. 2017

Oncotarget

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Receptor tyrosine kinases (RTKs), especially VEGFR-2, TIE-2, and EphB4, play a crucial role in both angiogenesis and tumorigenesis. Moreover, complexity and heterogeneity of angiogenesis make it difficult to treat such pathological traits with single-target agents. Herein, we developed two classes of multi-target RTK inhibitors (RTKIs) based on the highly conserved ATP-binding pocket of VEGFR-2/TIE-2/EphB4, using previously reported BPS-7 as a lead compound. These multi-target RTKIs exhibited considerable potential as novel anti-angiogenic and anticancer agents. Among them, QDAU5 displayed the most promising potency and selectivity. It significantly suppressed viability of EA.hy926 and proliferation of several cancer cells. Further investigations indicated that QDAU5 showed high affinity to VEGFR-2 and reduced the phosphorylation of VEGFR-2. We identified QDAU5 as a potent multiple RTKs inhibitor exhibiting prominent anti-angiogenic and anticancer potency both in vitro and in vivo. Moreover, quinazolin-4(3H)-one has been identified as an excellent hinge binding moiety for multi-target inhibitors of angiogenic VEGFR-2, Tie-2, and EphB4.

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“…Compound 65 (Figure 12), a7‐azaindole derivative, synthesized by Daydé‐Cazals et al., [75] was considered to be potent multitarget kinase inhibitor as an anticancer agent because of its markedly broad antiproliferative effects against different types of cancer cell lines, such as the murine leukemia‐derived cell lines BaF3 WT (EC 50 =0.04 nM), BaF3 T3151 (EC 50 =1.8 nM) and human kidney cancer cell line Caki‐2 (EC 50 =22 nM). Furthermore, at a concentration of 100 nM, 65 showed excellent inhibitory activity against tested oncogenic kinases, and particularly inhibited the EGFR and PDGFRA kinases at 82 and 68 % inhibition, respectively.…”

Section: Multitargeted Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Recent Advances in the Discovery of Multitargeted Tyrosine Kinase Inhibitors as Anticancer Agents

Guo

2020

ChemMedChem

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The treatment of cancer has been one of the most significant challenges for the medical field. Further research on the signal transduction pathway of tumor cells is driving the rapid development of antitumor agents targeting tyrosine kinases. However, most of the currently approved tyrosine kinase inhibitors based on the “single target/single drug” design are becoming less and less effective in the treatment of complex, heterogeneous, and multigenic cancers; this also results in resistance to chemotherapy. In contrast, multitargeted tyrosine kinase inhibitors (MT‐TKIs) can effectively block multiple pathways of intracellular signal transduction. Therefore, they have therapeutic advantages over single‐targeted inhibitors and have become a hotspot in antitumor drug research in recent years. This minireview summarizes recent advances in the discovery of MT‐TKIs based on their chemical structures. In particular, we describe the kinase inhibitory and antitumor activity of promising compounds, as well as their structure – activity relationships (SARs).

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Rational Design, Synthesis, and Biological Evaluation of 7-Azaindole Derivatives as Potent Focused Multi-Targeted Kinase Inhibitors

Cited by 48 publications

References 19 publications

In silico-based vaccine design against Ebola virus glycoprotein

In silico-based vaccine design against Ebola virus glycoprotein

Discovery and evaluation of triple inhibitors of VEGFR-2, TIE-2 and EphB4 as anti-angiogenic and anti-cancer agents

Recent Advances in the Discovery of Multitargeted Tyrosine Kinase Inhibitors as Anticancer Agents

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