Ivo efficacy, it really is an ideal lead compound for additional development of potent and selective activators of SIRT6 with enhanced bioavailability that may be promoted for the clinical phase. 4.2. SIRT6 Inhibitors Given the double-faced involvement of SIRT6 in cancer and inflammation, the inhibition of SIRT6 in specific contexts may possibly also represent a effective approach for cancer therapy. Indeed, inhibitors might target diverse SIRT6-mediated pathways contributing to cancer progression including DNA repair mechanisms, cell differentiation and inflammatory response (Table 4).Cancers 2021, 13,14 ofTable 4. Most relevant SIRT6 inhibitors.Compound Structure Impact on SIRT6 Activity Cellular and In Vivo Effects Reference(s)9b BHJH-TMIC50 = 8.1 (demyristoylation)SIRT6 inhibition and decreased TNF- fatty acylation in HEK293T cells.[114]11b OSS_IC50 = 89 (deacetylation)12bIC50 = 37 (deacetylation)13b IC50 = 22 (deacetylation)Augmented H3K9 acetylation and TNF- secretion in BxPC3 cells. GLUT1 upregulation and consequent elevated glucose uptake in L6 rat myoblasts and BxPC3 cells. Sensitization of MM cell lines to DNA-damaging agents. Suppression of DLBCL cell proliferation; induction of apoptosis and cell cycle arrest. Tumor growth reduction in DLBCL mouse xenograft. Enhanced H3K9 acetylation in BxPC3. Augmented glucose uptake in L6 rat myoblasts and BxPC3 cells. Sensitization of BxPC3 cells to gemcitabine. Enhancement of olaparib anticancer activity in Capan-1 cells. Elevated H3K9 acetylation and glucose uptake in PBMCs. Impaired TNF- secretion and T lymphocyte proliferation. Sensitization of pancreatic cancer cells to gemcitabine. Enhance of DNA-damage markers and telomere-dysfunction induced foci in HUVECs. Reduction in TNF- levels. Dose-dependent increase of H3K9 and H3K18 acetylation levels in BxPC-3 cells. Elevated GLUT-1 expression levels. Reduction of blood glucose content material in a mouse model of type 2 diabetes.[115][96] [91][116][117]14a A127-(CONHPr)BIC50 = six.7 (demyristoylation)[118]15 IC50 = 4.93 (deacetylation)[119]Product-based inhibitors like nicotinamide (7a) and its derivatives, as well as ADP-ribose (eight) (Figure 5) presented IC50 values inside the mid-micromolar range, while the IL-1 Antagonist MedChemExpress selectivity was absent or not tested. Nicotinamide showed IC50 values for the demyristoylation activity involving 73 and 184 according to the assay conditions [120,121]. Nicotinamide derivatives based on pyrazinamide showed improved SIRT6 inhibitory activity: 5-MeO-PZA (7b) and 5-Cl-PZA (7c) had IC50 values of 40.four and 33.two , respectively [122]. ADP-ribose (8) also inhibits SIRT6 activity and shows higher potency than nicotinamide with IC50 values of 74 (deoctanoylation) and 89 (demyristoylation), compared to values of 150 and 120 , respectively, for nicotinamide [123].Cancers 2021, 13,15 ofFigure five. Product- (7) and substrate-based (90) SIRT6 inhibitors.Another class of inhibitors directly Aurora A Inhibitor custom synthesis connected to the SIRT6 enzymatic mechanism of action are N -thioacyl-lysine-containing peptides, which lock the catalytic cycle at the initially step, i.e., the nucleophilic attack towards the (thio)carbonyl on the acyl group [124]. Thiomyristoyl peptides BHJH-TM1 (9a), BHJH-TM3 (9b), and BH-TM4 (9c) (Figure five) are depending on identified SIRT6 substrates (i.e., TNF–K20, TNF–K19 and H3K9 peptides) [114]. Their IC50 values for demyristoylation had been 2.8 , eight.1 and 1.7 , respectively, though they lacked selectivity because of the concomitant inhibition of SIRT1-3. 9c.
