A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors
Abstract
:1. Introduction
2. HDAC8 Is a Class I HDAC Enzyme
- HDAC8 is an X-linked protein which acts independently, e.g., without forming any co-complexes for the activity;
- The L1 loop of HDAC8 is closest to the enzyme active site and undergoes conformational changes, differently depending on the substrate (Figure 2);
- L1 and L6 form a specific pocket which requires an “L” shape conformation for selective binding (Figure 2);
- HDAC8 presents a nuclear localization sequence between the catalytic domain of the enzyme and the serine binding motif found at the end of the catalytic domain [24].
2.1. HDAC8 Substrates
2.1.1. SMC3
2.1.2. p53
2.1.3. ERRα
2.1.4. inv(16)
2.1.5. CREB
3. Involvement of HDAC8 in Different Diseases
3.1. X-Linked Disorders
3.1.1. Cornelia de Lange Syndrome (CdLS)
3.1.2. Duchenne Muscular Dystrophy (DMD)
3.2. Aberrant Wound Healing
3.2.1. Pulmonary Fibrosis (PF)
3.2.2. Renal Fibrosis
3.2.3. Liver Fibrosis
3.2.4. Cardiac Fibrosis
3.2.5. Aberrant Wound Healing Associated with Diabetic Foot Ulcers (DFU)
3.3. Cancer
3.3.1. Haematological Malignancies
3.3.2. Solid Tumours
4. Neuropathological Disorders and Conditions
4.1. HDACis Drug Design
4.2. HDAC8 Drug Design
5. HDAC8 Inhibitors
5.1. HDAC8is Bearing Hydroxamic Acids as ZBG
5.1.1. Aromatic-Based Linkers
5.1.2. Flexible Aliphatic-Based Linkers
5.1.3. Alkenyl-Based Linkers
IC50 (μM) 2 | 40 R1 = H- | 41 R1 = Br- | 12 R1 = Ph- |
---|---|---|---|
HeLa HDACs 1 | >10 | >10 | >10 |
hHDAC1 | ND | 4.5 ± 0.1 | 3.0 ± 0.2 |
hHDAC2 | ND | >20 | >20 |
hHDAC3 | ND | 4.8 ± 0.5 | 3.0 ± 0.1 |
hHDAC4 | ND | >20 | >20 |
hHDAC6 | ND | >20 | >20 |
hHDAC8 | 0.724 ± 0.0001 | 0.0057 ± 0.0001 | 0.027 ± 0.003 |
hHDAC10 | ND | >20 | >20 |
hHDAC11 | ND | >20 | >20 |
5.1.4. Linkerless HDAC8 Inhibitors
5.2. HDAC8is Bearing Novel ZBGs
6. Multi-Target Pharmacological Tools Acting on HDAC8
6.1. Multi-Drug Combinations Targeting HDAC8
6.2. Polypharmacological Tools Targeting HDAC8
6.2.1. Selective HDAC6/8 Dual Inhibitors
6.2.2. Selective HDAC6/8/10 Multi-Target Inhibitors
6.2.3. HDAC1-3/8 Dual Inhibitors
6.2.4. Tubulin Polymerization and HDAC8 Dual Inhibitors (TP/HDAC8is)
6.2.5. MMP2/HDAC8 Dual Inhibitors
6.2.6. Bromodomain BRPF1 and HDAC8 Dual Inhibitors
6.2.7. Selective HDAC8-Degrading PROTACs
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Cpds | R1 | hHDAC2 IC50 (μM) | hHDAC3/NCoR1 IC50 (μM) | hHDAC8 IC50 (μM) |
---|---|---|---|---|
14 | H- | 20 | 18 | 0.052 |
15 | 6.3 | 6.2 | 0.029 | |
16 | 3.6 | 15 | 0.023 |
Cpds | R1 | X | Ar | hHDAC1 IC50 (μM) | hHDAC2 IC50 (μM) | hHDAC4 IC50 (μM) | hHDAC6 IC50 (μM) | hHDAC8 IC50 (μM) |
---|---|---|---|---|---|---|---|---|
17 | Ph | -CH2 | 41 | 65 | 30 | 7.9 | 0.35 | |
18 | Ph | -CH2CH2 | >100 | 76 | >100 | 3.2 | 0.18 | |
13 | Ph | -SCH2 | 38 | >100 | 44 | 2.4 | 0.070 | |
19 | -CH2CH2 | >100 | >100 | >100 | 1.1 | 0.10 | ||
20 | Ph | -SCH2 | >100 | >100 | >100 | 2.2 | 0.053 | |
7 | Ph | -SCH2 | >100 | >100 | >100 | 14 | 0.15 |
Cpds | R1 | X | Y | hHDAC1 IC50 (μM) 1 | hHDAC6 IC50 (μM) 1 | hHDAC8 IC50 (μM) 1 |
---|---|---|---|---|---|---|
21 | Cl | -NH | Me | 18.7 ± 2.5 | 14.4 ± 2.4 | 0.035 ± 0.04 |
22 | H | -NH | -OMe | 14.5 ± 1.4 | 5.1 ± 0.8 | 0.069 ± 0.017 |
23 | H | -O | -OMe | 12.1 ± 5.7 | 2.9 ± 0.3 | 0.027 ± 0.03 |
Cpds | R1 | hHDAC2 IC50 (μM) 1 | hHDAC6 IC50 (μM) 1 | hHDAC8 IC50 (μM) 1 |
---|---|---|---|---|
24 | 14.5 ± 2.4 | 1.5 ± 0.3 | 0.050 ± 0.010 | |
25 | 47.1 ± 7.0 | 2.6 ± 0.5 | 0.080 ± 0.020 | |
26 | 11.2 ± 1.8 | 1.8 ± 0.3 | 0.060 ± 0.010 |
Cpds | R1 | R2 | X | hHDAC3 IC50 (μM) | hHDAC6 IC50 (μM) | hHDAC8 IC50 (μM) | hHDAC11 IC50 (μM) |
---|---|---|---|---|---|---|---|
27 | 3-tBu | H | >1 | 0.066 | 0.0337 | >1 | |
28 | 3-tBu | >1 | >1 | 0.0835 | >1 | ||
29 | 3-tBu | >1 | >1 | 0.0660 | >1 | ||
30 | 3,5-CF3 | >1 | >1 | 0.0234 | >1 | ||
31 | 3-OCF3 | >1 | >1 | 0.0655 | >1 |
Cpds | hHDAC1 IC50 (μM) 1 | hHDAC2 IC50 (μM) 1 | hHDAC3 IC50 (μM) 1 | hHDAC6 (% Inhibition) 2 | hHDAC8 IC50 (μM) 1 |
---|---|---|---|---|---|
34 | 33 ± 1.1 | 2.7 ± 0.67 | 52 ± 3.0 | 97 ± 0.050 | 1.4 ± 0.41 |
35 | 27 ± 3.7 | >100 | >100 | 21 ± 0.040 | 0.082 ± 0.019 |
36 | 7.3 ± 0.48 | 47 ± 17 | 38 ± 2.2 | 39 ± 1.2 | 0.055 ± 0.014 |
Cpds | R | X | HeLa HDACs IC50 (μM) 1 | hHDAC3/NCoR1 (% Inhibition) 2 | hHDAC8 IC50 (μM) |
---|---|---|---|---|---|
37 | -CH- | 3.57 ± 2.19 | 4.21 | 3.14 ± 1.01 | |
38 | -N- | 3.65 ± 2.39 | 4.42 | 1.74 ± 0.81 | |
39 | -N- | 4.99 ± 1.82 | 5.35 | 4.29 ± 1.42 |
Cpds | R1 | R2 | X | n | hHDAC1 IC50 (μM) | hHDAC2 IC50 (μM) | hHDAC3 IC50 (μM) | hHDAC6 IC50 (μM) | hHDAC8 IC50 (μM) |
---|---|---|---|---|---|---|---|---|---|
48 | H- | H- | -N- | 3 | 3.6 ± 0.8 | 32 ± 15 | >50 | 6.7 ± 0.8 | 0.011 ± 0.001 |
49 | H- | F- | -N- | 3 | 35 ± 3 | >50 | >50 | 5.2 ± 1.1 | 0.017 ± 0.0001 |
50 | Br- | H- | -S- | 2 | >50 | >50 | >50 | >50 | 0.260 |
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Fontana, A.; Cursaro, I.; Carullo, G.; Gemma, S.; Butini, S.; Campiani, G. A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors. Int. J. Mol. Sci. 2022, 23, 10014. https://doi.org/10.3390/ijms231710014
Fontana A, Cursaro I, Carullo G, Gemma S, Butini S, Campiani G. A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors. International Journal of Molecular Sciences. 2022; 23(17):10014. https://doi.org/10.3390/ijms231710014
Chicago/Turabian StyleFontana, Anna, Ilaria Cursaro, Gabriele Carullo, Sandra Gemma, Stefania Butini, and Giuseppe Campiani. 2022. "A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors" International Journal of Molecular Sciences 23, no. 17: 10014. https://doi.org/10.3390/ijms231710014