Pharmacological Advantage of SIRT2-Selective versus pan-SIRT1–3 Inhibitors

Abstract

Because of their involvement in various biological pathways, the sirtuin enzyme family members SIRT1, SIRT2, and SIRT3 play both tumor-promoting and tumor-suppressing roles, based on the context and experimental conditions. Thus, an interesting question is whether inhibiting one of them or inhibiting all of them would be better for treating cancers. Pharmacologically, this is difficult to address, due in part to potential off-target effects of different compounds. Compounds with almost identical properties but differing in SIRT1–3 selectivity will be useful for addressing this question. Here, we have developed a pan SIRT1–3 inhibitor (NH4-6) and a SIRT2-selective inhibitor (NH4-13) with very similar chemical structures, with the only difference being the substitution of an ester bond to an amide bond. Such a minimal difference allows us to accurately compare the anticancer effect of pan SIRT1–3 inhibition and SIRT2-selective inhibition in cellular and mouse models. NH4-6 showed stronger cytotoxicity than NH4-13 in cancer cell lines. In mice, both inhibitors showed similar anticancer efficacy. However, NH4-6 is toxic to mice, which hinders the use of higher dosages. These results highlight the advantage of SIRT2-selective inhibitors as potential anticancer therapeutics.

Sirtuin Modulators in Cellular and Animal Models of Human Diseases

“…Furthermore, in cells, NH4-6 increased acetylation levels of p53, α-tubulin, and IDH2, acetylation targets of SIRT1, SIRT2, and SIRT3, respectively. Meanwhile, NH4-13 increased the acetylation levels of alpha-tubulin, but not of p53 and IDH2 (Hong et al, 2021).…”

“…In HCT-116 colorectal cancer cells, AF8 increased the acetylation of α-tubulin in a dose-dependent manner but did not change the acetylation of p53 (Farooqi et al, 2019). Two other TM derivatives, NH4-6 and NH4-13 containing a trimethylammonium moiety (Hong et al, 2021), have excellent aqueous solubility compared to TM. The difference between the two inhibitors is that NH4-6 has an amide linkage and NH4-13 has an ester linkage between the lysine and the trimethylammonium moiety.…”

“…Overall, NH4-6 and NH4-13 had similar anticancer effects, but NH4-13, due to its SIRT2 selectivity, has much lower toxicity in vivo. Therefore, it could be advantageous to use SIRT2-selective inhibitors to treat cancers (Hong et al, 2021).…”

Protein acetylation effects on enzyme activity and metabolic pathway fluxes

“…Therefore, sirtuins appear to have contradictory roles in cancer and clearly further research is needed to elucidate their regulatory function in sick and healthy cells. To this end, several molecules have been designed to act as sirtuin modulators and hence as anticancer drugs in the near future 91 …”

“…Cytosolic SIRT2 knockout mice develop more tumors when they get old; then, SIRT2 may act as a tumor suppressor. However, SIRT2 deacetylates several metabolic enzymes (LDH‐A), transcription factors (c‐MYC, Slug, and KRas4a), and signaling proteins to promote tumorigenesis 52,91,93 …”