Checking NEKs: Overcoming a Bottleneck in Human Diseases
Abstract
:1. Introduction
2. NEK1
3. NEK2
4. NEK3
5. NEK4
6. NEK5
7. NEK6
8. NEK7
9. NEK8
10. NEK9
11. NEK10
12. NEK11
13. Pharmacological Inhibitors of the NEK Family
14. Conclusions
Funding
Conflicts of Interest
References
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Drug Name | Chemical Formula | NEK Targets | Action/Effects | Stage of Development | Selectivity | References |
---|---|---|---|---|---|---|
Fostamatinib | C23H26FN6O9P | NEK1 NEK3 NEK4 NEK5 NEK9 NEK11 | Inhibits signal transduction by Fcγ receptors involved in the antibody-mediated destruction of platelets. NEKs 1,2,3,4 5,9,11 are included in the list of targets | Approved for the treatment of chronic immune thrombocytopenia (ITP). Under investigation for other diseases | The active metabolite of fostamatinib, named R406, presents a lack of selectivity among several kinases | [203] |
5-[(Z)-(5-Chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene) methyl]-N,2,4-trimethyl-1H-pyrrole-3-carboxamide | C17H16ClN3O2 | NEK2 | Interacts with NEK2 | Experimental | No off-targets have been described | [204] |
NCI code 51,525 and 58991 | - | NEK2 | Inhibits NEK2 | Experimental | No off-targets have been described | [205] |
MBM-17 and MBM-55 | C28H29N6 and C28H28N6O2F respectively | NEK2 | Inhibits NEK2 and has antiproliferative/antitumor properties | Experimental | It has low nanomolar activity and a great selectivity for NEK2 | [206] |
di-demethylchlorpromazine and 2-[5-fluoro-1H-indol-3-yl] propan-1-amine | C15-H15-Cl-N2-S.Cl-H and C11H14ClFN2 respectively | NEK2 | Inhibits NEK2 | Pre-experimental (in silico) | No off-targets have been described | [207] |
(5Z)-2-hydroxy-4-methyl-6-oxo-5-[(5-phenylfuran-2-yl)methylidene]-5,6-dihydropyridine-3-carbonitrile) or compound 8 | C22H24F3N8O2 | NEK6 NEK1 | Inhibits NEK6. Displays anti-proliferative effects on several cancer cell lines with low IC50 values. Induces cell cycle arrest in the G2/M phases and has a synergistic effect with cisplatin and paclitaxel in ovarian cancer. It can inhibit NEK1. | Experimental | Inhibits NEK6 and NEK1. No off-targets have been described | [208] |
Metformin | C4H11N5 | NEK7 | Metformin inhibits NEK7 expression in an experimental diabetic periodontitis model | Approved for type II diabetes | Activates AMPK, inhibits electron transfer flavoprotein-ubiquinone oxidoreductase (ETFDH), and glycerol-3-phosphate dehydrogenase [NAD(+)] (GPD1) | [175,209,210,211] |
Ethyl 1-(2-hydroxypentyl) 5-(3-(3-(trifluoromethyl) phenyl)ureido)-1H-pyrazole-4-carboxylate or GeGe3 | - | NEK10 | Screening for GeGe3-targeted kinases revealed NEK10 as candidate targets, such as Aurora B. Inhibits physiological and tumor angiogenesis. | Experimental | Strongly inhibits aurora B, aurora C, NEK 10, polo like kinases 2 and 3 (PLK2/PLK3), dystrophia myotonica protein kinase 1 (DMPK), and calcium/calmodulin-dependent protein kinase type 1 (CaMK1) | [212] |
Dabrafenib | C23H20F3N5O2S2 | NEK11 | Reduces the proliferation and regression of tumors in xenograft models. | Approved for the treatment of metastatic melanoma with BRAF V600E mutations | Inhibits serine/threonine-protein kinase B-raf (BRAF1), proto-oncogene c-RAF (RAF), serine/threonine-protein kinase SIK1 (SIK-1), NEK11, and LIM domain kinase 1 (LIMK-1) | [213,214] |
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Peres de Oliveira, A.; Kazuo Issayama, L.; Betim Pavan, I.C.; Riback Silva, F.; Diniz Melo-Hanchuk, T.; Moreira Simabuco, F.; Kobarg, J. Checking NEKs: Overcoming a Bottleneck in Human Diseases. Molecules 2020, 25, 1778. https://doi.org/10.3390/molecules25081778
Peres de Oliveira A, Kazuo Issayama L, Betim Pavan IC, Riback Silva F, Diniz Melo-Hanchuk T, Moreira Simabuco F, Kobarg J. Checking NEKs: Overcoming a Bottleneck in Human Diseases. Molecules. 2020; 25(8):1778. https://doi.org/10.3390/molecules25081778
Chicago/Turabian StylePeres de Oliveira, Andressa, Luidy Kazuo Issayama, Isadora Carolina Betim Pavan, Fernando Riback Silva, Talita Diniz Melo-Hanchuk, Fernando Moreira Simabuco, and Jörg Kobarg. 2020. "Checking NEKs: Overcoming a Bottleneck in Human Diseases" Molecules 25, no. 8: 1778. https://doi.org/10.3390/molecules25081778