Role and mechanistic actions of protein kinase inhibitors as an effective drug target for cancer and COVID

Janakiraman, N.; Tamilanban, T.; Kumar, Pradeep; Guru, Ajay; Muthupandian, Saravanan; Kathiravan, Muthu K.; Arockiaraj, Jesu

doi:10.1007/s00203-023-03559-z

Cited by 2 publications

(2 citation statements)

References 117 publications

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“…Molecular modeling has provided further insights, particularly that the active and inactive compounds adopt different binding modes in the respective binding sites, clearly showing different interaction patterns with the binding site amino acid residues. Recent studies have shown that targeted therapy against different cancers could be a therapeutic option against cancer-specific cells and toward the signaling pathways is a valuable avenue of research [ 46 ] The kinase family of anticancer drug targets is also known to provide a valuable source of biological targets against both cancers and COVID infections [ 47 ]. As an example, kinases like the tyrosine kinases, Rho kinase, Bruton tyrosine kinase, ABL kinases, and NAK kinases play an important role in the modulation of signaling pathways involved in both cancers and viral infections such as COVID [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Design, synthesis, and biochemical and computational screening of novel oxindole derivatives as inhibitors of Aurora A kinase and SARS-CoV-2 spike/host ACE2 interaction

Eni,

Cassel,

Namba-Nzanguim

et al. 2024

Med Chem Res

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Isatin (indol-2,3-dione), a secondary metabolite of tryptophan, has been used as the core structure to design several compounds that have been tested and identified as potent inhibitors of apoptosis, potential antitumor agents, anticonvulsants, and antiviral agents. In this work, several analogs of isatin hybrids have been synthesized and characterized, and their activities were established as inhibitors of both Aurora A kinase and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike/host angiotensin-converting enzyme II (ACE2) interactions. Amongst the synthesized isatin hybrids, compounds 6a, 6f, 6g, and 6m exhibited Aurora A kinase inhibitory activities (with IC50 values < 5 $$\mu$$ μ M), with GScore values of −7.9, −7.6, −8.2 and −7.7 kcal/mol, respectively. Compounds 6g and 6i showed activities in blocking SARS-CoV-2 spike/ACE2 binding (with IC50 values in the range < 30 $$\mu$$ μ M), with GScore values of −6.4 and −6.6 kcal/mol, respectively. Compounds 6f, 6g, and 6i were both capable of inhibiting spike/ACE2 binding and blocking Aurora A kinase. Pharmacophore profiling indicated that compound 6g tightly fits Aurora A kinase and SARS-CoV-2 pharmacophores, while 6d fits SARS-CoV-2 and 6l fits Aurora A kinase pharmacophore. This work is a proof of concept that some existing cancer drugs may possess antiviral properties. Molecular modeling showed that the active compound for each protein adopted different binding modes, hence interacting with a different set of amino acid residues in the binding site. The weaker activities against spike/ACE2 could be explained by the small sizes of the ligands that fail to address the important interactions for binding to the ACE2 receptor site.

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Section: Discussionmentioning

confidence: 99%

Design, synthesis, and biochemical and computational screening of novel oxindole derivatives as inhibitors of Aurora A kinase and SARS-CoV-2 spike/host ACE2 interaction

Eni,

Cassel,

Namba-Nzanguim

et al. 2024

Med Chem Res

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“…VEGF ligands bind to three different tyrosine kinases (VEGFR-TK): FLT-1 (FLT1), FLT-2 (KDR/FLK1) and FLT-4 (FLT4) [ 11 ]. VEGFR-2 is activated by the unique binding of VEGF generated by endothelial cells [ 12 ] and many malignancies have VEGFR-2 amplification [ 13 ]. Series of VEGFR-2 inhibitors have recently been approved for the management of numerous cancers such as Sorafenib ( I ) [ 14 ], Lenvatinib ( II ) [ 15 ] and Sunitinib ( III ) [ 16 ] with IC 50 = 90, 1 and 10 nM, respectively, as well as urea-based heterocycles IV (IC 50 = 1.5 µM) [ 17 ] and V (IC 50 = 6.2 nM) [ 18 ] ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Assessment of N′-(2-Oxoindolin-3-ylidene)-6-methylimidazo[2,1-b]thiazole-5-carbohydrazides as Potential Anti-Proliferative Agents toward MCF-7 Breast Cancer

Alshaye,

Elgohary,

Elkotamy

et al. 2024

Pharmaceuticals

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Breast cancer is a serious threat to the health and lives of women. Two novel series of N′-(2-oxoindolin-3-ylidene)-6-methylimidazo[2,1-b]thiazole-5-carbohydrazides and 1-(aryl)-3-(6-methylimidazo[2,1-b]thiazol-5-yl)ureas were designed, synthesized and investigated for their anticancer efficacy against the MCF-7 breast cell line. Three compounds of the first series showed potent activity toward MCF-7 with IC50 in the range 8.38–11.67 µM, respectively, as compared to Sorafenib (IC50 = 7.55 µM). N′-(1-butyl-2-oxoindolin-3-ylidene)-6-methylimidazo[2,1-b]thiazole-5-carbohydrazide inhibited VEGFR-2 with IC50 = 0.33 µM when compared with Sorafenib (IC50 = 0.09 µM). Furthermore, this compound was introduced to PCR assessment, where it increased Bax, caspase 8, caspase 9 and cytochrome C levels by 4.337-, 2.727-, 4.947- and 2.420-fold, respectively, while it decreased levels of Bcl-2, as the anti-apoptotic gene, by 0.359-fold when compared to the untreated control MCF-7. This compound was also arrested in the G2/M phase by 27.07%, compared with 11.31% for the control MCF-7. Furthermore, it induced early and late apoptosis in MCF-7. In addition, a molecular docking study in the VEGFR-2 active site was performed to assess the binding profile for the most active compounds. Moreover, ADME parameters of the targeted compounds were also evaluated.

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Role and mechanistic actions of protein kinase inhibitors as an effective drug target for cancer and COVID

Cited by 2 publications

References 117 publications

Design, synthesis, and biochemical and computational screening of novel oxindole derivatives as inhibitors of Aurora A kinase and SARS-CoV-2 spike/host ACE2 interaction

Design, synthesis, and biochemical and computational screening of novel oxindole derivatives as inhibitors of Aurora A kinase and SARS-CoV-2 spike/host ACE2 interaction

Design, Synthesis and Biological Assessment of N′-(2-Oxoindolin-3-ylidene)-6-methylimidazo[2,1-b]thiazole-5-carbohydrazides as Potential Anti-Proliferative Agents toward MCF-7 Breast Cancer

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