Nek2 Kinase Signaling in Malaria, Bone, Immune and Kidney Disorders to Metastatic Cancers and Drug Resistance: Progress on Nek2 Inhibitor Development
Abstract
:1. Introduction
2. Nek2 Signaling in Normal Human Physiology
3. The Nek2 Kinase in Polycystic Kidney Diseases (PKDs), Chromosomal Instability and Drug Resistance, Bone Destruction, and the DNA Damage Response Pathway
4. The Nek2 Kinase in Oncogenesis and Metastatic Signaling
5. Global Proteomic and Phosphoproteomic Data and Activation of the Nek2 Kinase in Cancers
6. Nek2 Ortholog in Malaria
7. Small Molecule Inhibitors of the Human Nek2 Kinase
- (a)
- (b)
- (c)
- (d)
- (e)
- (f)
- Type V: Chemotypes that occupy two distinct sites at once. This type of inhibitor has been further divided into two subcategories. These are (i) Bisubstrate analog inhibitors, which span over the ATP and substrate-binding site and (ii) Bivalent inhibitors, which span over the ATP-binding site along with any other site on the protein except at the substrate binding site [179,182].
- (g)
- Type VI: Chemotypes with a built-in electrophilic warhead that trap the accessible nucleophilic protein residue to form a covalent adduct with the target kinase [179].
8. ATP-Site Binding Inhibitors of Nek2
8.1. Pyrrole-Indoline-Based Ligand
8.2. Thiophene-Based Ligands
8.3. Viridin/Wortmannin-like Ligands
8.4. Aminopyrazine Inhibitors
8.5. Benzimidazole Inhibitors (DFG-Out)
8.6. Oxyindole-Propynamide Inhibitors
8.7. Aminopyridine Inhibitors
8.8. Quinoline-Based Inhibitors
8.9. Pyrimidine Inhibitors
8.10. Imidazo[1,2-a] Pyridine Inhibitors
8.11. Purine Inhibitors
8.12. Protein-Protein Interaction (PPI) Inhibitors
9. Expert Opinion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Entry # | Chemical Structure | Inhibition Profile with the Compound I.D. (In Parenthesis) | Special Notes and Reference | Inhibitor Type |
---|---|---|---|---|
1 | | IC50 (SU11652): 8 µM IC50 (SU11248): 12 µM | The first reported non-selective and cell-permeable chemotype that binds to the inactive conformation of Nek2 [140]. | Type II |
2 | | IC50 (2a): 21 µM IC50 (2b): 25 µM | Thiophene-based inhibitors, originally developed for targeting PLK1, emerged as potential Nek2 inhibitory scaffold [141]. | NA |
3 | | IC50 (3a): 1.4 µM IC50 (3b): 4.4 µM | Cell-active Nek2 inhibitors that showed significant Nek2 selectivity when compared to Nek6 and Nek7 but not toward Aurora A, Plk 1, and Cdk1. Affected centrosome separation in Nek2-inducible human tumor cells [142]. | Type VI $ |
4 | | IC50 (4): 0.23 µM | Inhibits Nek2 by inducing notable conformational changes, “Tyr-down”, in protein. Non-selective and suffers from poor cell-permeability [143]. | NA |
5 | | IC50 (5): 0.36 µM | The first benzimidazole-type inhibitor to induce DFG-out conformation in Nek2 kinase. Although it exhibited remarkable selectivity over Plk1, it failed to maintain the selectivity when tested against other kinases. It also suffered from the lack of cellular potency [144]. | Type II |
6 | | IC50 (6): 0.77 µM | The first developed irreversible inhibitor of Nek2 with cellular activity which covalently modifies the protein by trap** Cys22 [145]. | Type VI |
7 | | IC50 (7): 0.022 µM | A cell permeable Nek2 inhibitor with improved selectivity that induces a DFG-out conformation of protein [146]. | Type II |
8 | | IC50: (Pelitinib/EKB-569): 661 nM IC50: (Neratinib/HKI-272): 247 nM | Using a whole-animal-based Nek2 overexpression model in flies, two cell active EGFR inhibitors were found to be active against Nek2 kinase [69]. | NA |
9 | | IC50 (HCI-2389): 0.016 µM | Highly potent and cell-active Nek2 inhibitor that effectively sensitized bortezomib-resistant multiple myeloma cells [147]. | Type VI |
10 | | IC50 (MBM-5): 0.34 µM | Effectively inhibited Nek2 kinase in leukemia and gastric and colorectal cancer cell lines and retained its efficacy while being evaluated in vivo using MGC-803 gastric and HCT-116 xenografts in mouse models. Although promising, MBM-5 suffered from unimpressive pharmacokinetic profile [148]. | NA |
11 | | IC50 (CMP3a): 0.082 µM | Disrupts the Nek2-EZH2 nexus in glioma stem cells and silenced tumor in xenotransplanted mouse. Poor pharmacokinetic profile of CMP3a only allowed it to be used as a chemical tool and not as a therapeutic modality [149]. | NA |
12. | | IC50 (12a): 0.62 µM IC50 (12b): 0.27 µM | First inhibitor of its kind to invoke DFG-in configuration in Nek2 kinase [150]. Most potent analog of this series. Despite notable potency, it failed to become a therapeutic candidate due to instability reasons under physiological conditions. | Type I 1/2 |
13 | | IC50 (13): 0.062 µM | A cell-active irreversible inhibitor of Nek2 kinase that showed modest selectivity profile over several other kinases; however, it lacked a desirable pharmacokinetic (PK) profile [151]. | Type VI |
14 | | IC50 (INH1): NA | First discovered 2-aminothiazole-based PPI inhibitor of Hec1/Nek2 axis with cellular activity [45]. | NA |
15 | | IC50 (15): NA | Second generation of cell-permeable thiazole derivatives that affected Hec1/Nek2 activity [47]. | NA |
16 | | IC50 (INH154): NA | Third generation thiazole-derivative with little or no toxicity that suppressed tumor growth effectively in mouse xenograft model upon peritoneal administration [47]. | NA |
17 | | IC50 (TH-39): NA | A cell-active 2-aminothiazole derivative that exhibited the hallmark of Hec1/Nek2 inhibition [46,152]. | NA |
18 | | IC50 (TAI-1): NA | The first orally administered Hec1/Nek2 inhibitor—also effective when administered intravenously—with little or no adverse effect. It showed tremendous promise in suppressing tumor growth in mouse model [153]. | NA |
19 | | IC50 (19): NA | Extremely potent Hec1/Nek2 disruptor that presented a high AUC when administered in SD rats [154]. | NA |
20 | | IC50 (TAI-95): NA IC50 (T-1101 tosylate): NA | A very potent HEC1/Nek2 inhibitor with impressive pharmacological profile that is currently being evaluated in clinical trials [155,156,157]. | NA |
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Dana, D.; Das, T.; Choi, A.; Bhuiyan, A.I.; Das, T.K.; Talele, T.T.; Pathak, S.K. Nek2 Kinase Signaling in Malaria, Bone, Immune and Kidney Disorders to Metastatic Cancers and Drug Resistance: Progress on Nek2 Inhibitor Development. Molecules 2022, 27, 347. https://doi.org/10.3390/molecules27020347
Dana D, Das T, Choi A, Bhuiyan AI, Das TK, Talele TT, Pathak SK. Nek2 Kinase Signaling in Malaria, Bone, Immune and Kidney Disorders to Metastatic Cancers and Drug Resistance: Progress on Nek2 Inhibitor Development. Molecules. 2022; 27(2):347. https://doi.org/10.3390/molecules27020347
Chicago/Turabian StyleDana, Dibyendu, Tuhin Das, Athena Choi, Ashif I. Bhuiyan, Tirtha K. Das, Tanaji T. Talele, and Sanjai K. Pathak. 2022. "Nek2 Kinase Signaling in Malaria, Bone, Immune and Kidney Disorders to Metastatic Cancers and Drug Resistance: Progress on Nek2 Inhibitor Development" Molecules 27, no. 2: 347. https://doi.org/10.3390/molecules27020347