Table 2 Most relevant sirtuin inhibitors

1 ,

splitomicin

ySir2 IC₅₀ = 60 μM

SIRT1: no inhibition @500 μM

Minimal inhibitory concentration (MIC) in yeast of 0.49 μM.

[37]

2,

HR-73

SIRT1 IC₅₀ = < 5 μM

Decreased HIV transcription through viral Tat protein acetylation.

[38]

3, 4

3 SIRT2 IC₅₀ = 1.5 μM

4 SIRT2 IC₅₀ = 1.5 μM (racemate)

SIRT2 IC₅₀ = 1.0 μM (R enantiomer)

Weak antiproliferative effects and increased α-tubulin acetylation in MCF-7 breast cancer cells.

[39]

5,

EX-527, selisistat

SIRT1 IC₅₀ = 0.098 μM

SIRT2 IC₅₀ = 19.6 μM

SIRT3 IC₅₀ = 48.7 μM

Induction of p53 acetylation in different cell lines.

Modulation of the acetylation status of the mutant huntingtin via SIRT1 inhbition shown to restore transcriptional dysregulation in models of Huntington’s disease (HD) treatment.

In a first Phase II clinical trial found to be safe and well tolerated in early stage HD patients at plasma levels within the therapeutic concentration range in preclinical HD models.

[40–44]

6,

cambinol

SIRT1 IC₅₀ = 56 μM

SIRT2 IC₅₀ = 59 μM

SIRT3: no inhibition @300 μM

SIRT5: 42% inhibition @300 μM

Induces apoptosis in BCL6-expressing Burkitt lymphoma cells.

Reduces tumor growth of Burkitt lymphoma in a mouse xenograft model.

Reduces neuroblastoma formation in N-Myc transgenic mice.

[45–50]

7,

AGK2

SIRT1 IC₅₀ > 50 μM

SIRT2 IC₅₀ = 3.5 μM

SIRT3 IC₅₀ > 50 μM

Protective against Parkinson’s disease (PD) in different PD models.

Induces caspase-3-dependent apoptosis and necrosis of C6 glioma cells.

[24, 51]

8, tenovin-1

9, tenovin-6

Tenovin-1:

IC₅₀s not determined due to lack of water solubility

Tenovin-6:

SIRT1 IC₅₀ = 21 μM

SIRT2 IC₅₀ = 10 μM

SIRT3 IC₅₀ = 67 μM

Tenovin-6

Cytotoxic to the ARN8 melanoma cells.

Delayes the growth of xenograft tumors derived from ARN8 cells.

Decelerates the disease progression of chronic myelogenous leukemia in mice model.

Potent antitumor activity in various human gastric cancer cells via death receptor 5 (DR5) upregulation.

[52–54]

10,

sirtinol

ySir2 IC₅₀ = 70 μM

SIRT1 IC₅₀ = 131 μM

SIRT2 IC₅₀ = 49 μM

Inhibits the viability of MCF-7, H1299, DU145, PC3 and HeLa cells.

Enhances the chemosensitivity to camptothecin and cisplatin in DU145, PC3 and HeLa cells.

Promotes a signifcant growth inhibition or apoptosis in cells from adult T-cell leukemia-lymphoma (ATL) and HTLV-1-related cell lines.

[55–59]

11,

salermide

SIRT1 IC₅₀ = 43 μM

SIRT2 IC₅₀ = 25 μM

Induces apoptosis in various cancer lines (mainly MOLT4, KG1A, SW480, and Raji) but not in normal cells (MRC5) through inhibition of SIRT1 in a p53-independent manner.

Induces apoptosis in NSCLC cells through upregulation of CDR5.

Exerts potent antiproliferative effects on MOLT4, MDA-MB-231 and RKO cancer cells and in colorectal carcinoma (CRC) and glioblastoma multiforme (GBM) cancer stem cells (CSCs).

Exerts cell protection effects in a C. elegans model of muscular dystrophy.

Induces apoptosis and death of schistosomula, separation of adult worm pairs and reduction in egg laying, through inhibition of the S. mansoni specific sirtuin

[60–64]

12,

MC2141

SIRT1 IC₅₀ = 9.8 μM

SIRT2 IC₅₀ = 12.3 μM

Induces apoptosis in U937 cells.

Exerts significant antiproliferative effects on Raji , DLD1, HeLa, and CRC and GBM CSCs.

[65, 66]

13,

inauhzin

SIRT1 IC₅₀ = 0.7- 2 μM

SIRT2: no inhibition @50 μM

SIRT3: no inhibition @50 μM

Activates and stabilizes p53 by inhibiting SIRT1 activity with consequent p53 acetylation and prevention of MDM2-mediated p53 ubiquitylation.

Inhibits cell proliferation and promotes senescence and tumor-specific p53-dependent apoptosis without genotoxicity in different cell lines (mainly H460, HCT116, and A549 cells).

Represses the growth of xenograft tumors derived from p53-harbouring H460 and HCT116 cells.

[67]

14

SIRT1 IC₅₀ = 4 nM SIRT2 IC₅₀ = 1 nM

SIRT3 IC₅₀ = 7 nM

Not reported

[68]

15,

SirReal2

SIRT2 IC₅₀ = 0.14-0.44 μM

SIRT1 22% inhibition @100 μM

SIRT3 no inhibition @100 μM

SIRT4 no inhibition @200 μM

SIRT5 no inhibition @200 μM

SIRT6 19% inhibition @200 μM

Hyperacetylation of α-tubulin and of the microtubule network in HeLa cells (@20 μM).

Significant depletion of the SIRT2 substrate BubR1 (spindle assembly checkpoint protein) in HeLa cells.

No alteration of cell cycle distribution in HeLa cells.

[69]

16-20

16 SIRT2 IC₅₀ = 0.18 μM

SIRT1 29% inhibition @200 μM

17 SIRT2 IC₅₀ = 0.26 μM

SIRT1 no inhibition @200 μM

18 SIRT2 IC₅₀ = 0.21 μM

SIRT1 no inhibition @200 μM

19 SIRT2 IC₅₀ = 0.31 μM

SIRT1 no inhibition @200 μM

20 SIRT2 IC₅₀ = 0.32 μM

SIRT1 no inhibition @200 μM

Hyperacetylation of α-tubulin and of the microtubule network in HeLa cells (16 @10 μM).

[70]

21

SIRT2 IC₅₀ = 48.3 nM

SIRT1 IC₅₀ = 12 μM

SIRT3 IC₅₀ = 44.2 μM

Time-dependent and dose-dependent hyperacetylation of α-tubulin in MCF-7 cells.

Modest cytotoxic effects (CC₅₀ 26-33μM) in human cancer cell lines (MCF-7, K562 and DU145).

[71]

22, 23

22 SIRT2 IC₅₀ = 3.7 μM

23 SIRT2 IC₅₀ = 12.2 μM

SIRT1/3 no inhibition @200 μM

for both compounds

Dose-dependent hyperacetylation of α-tubulin in MCF-7 cells.

Dose-dependent antiproliferative effects on MCF-7 and A549 cancer cells.

[72, 73]

24,

AK-7

SIRT2 IC₅₀ = 15.5 μM

SIRT1/3 no inhibition @50 μM

Neuroprotective reduction of total neuronal cholesterol biosynthesis in a SIRT2 inhibition-dependent way.

Neuroprotective effects in different models of Huntington’s disease and Parkinson’s disease.

[74–76]

25,

SDX-437

SIRT3 IC₅₀ = 700 nM

SIRT1 no inhibition @100 μM

Not reported.

[77]

26

SIRT6 IC₅₀ = 89 μM

SIRT1 IC₅₀ = 1578 μM

SIRT2 IC₅₀ = 751 μM

Hyperacetylation of SIRT6 substrate H3K9 in pancreatic adenocarcinoma BxPC-3 cells.

Glucose uptake increase, dose-dependent upregulation of GLUT-1 expression and reduction of TNF-α secretion in BxPC-3 cells.

[78]

27, 28

27 SIRT1 IC₅₀ = 3.9 μM

28 SIRT1 IC₅₀ = 2.7 μM SIRT2 IC₅₀ = 23 μM

SIRT3 IC₅₀ > 100 μM

Not reported.

[84, 85]

29

SIRT1 IC₅₀ = 0.9 μM SIRT2 IC₅₀ = 3 μM

SIRT3 IC₅₀ = 8 μM

Antiproliferative effect in A549 lung carcinoma and MCF-7 breast carcinoma cell lines.

[86, 87]

30

SIRT1 IC₅₀ = 6 μM SIRT2 IC₅₀ = 26 μM

SIRT3 IC₅₀ = 29 μM

Antiproliferative effect in A549 lung carcinoma and MCF-7 breast carcinoma cell lines.

[86, 87]

31-33

31 SIRT1 IC₅₀ = 11 μM SIRT2 IC₅₀ = 77 μM

32 SIRT1 IC₅₀ = 12 μM SIRT2 IC₅₀ = 30 μM

33 SIRT1 IC₅₀ = 0.7 μM SIRT2 IC₅₀ = 4 μM

Not reported.

[88]