Uses
CHIC35, an analog of EX-527, is a potent and selective inhibitor of SIRT1 (IC50=0.124 μM). CHIC35 shows potential selective inhibition against SIRT1 over SIRT2 (IC50=2.8 μM) or SIRT3 (IC50>100 μM)[1]. CHIC35 has anti-inflammatory effects and can be used for CHARGE syndrome research[1][2].
Definition
ChEBI: CHIC-35 is an organic heterotricyclic compound resulting from the formal fusion of the 2-3 bond of 5-chloroindole with the 2-3 bond of cycloheptanecarboxamide (the S enantiomer). It is a potent, cell-permeable, metabolically stable and selective inhibitor of the deacetylase SIRT1. It has a role as an EC 3.5.1.98 (histone deacetylase) inhibitor. It is an aromatic compound, an organic heterotricyclic compound, an organochlorine compound and a primary carboxamide.
General Description
A cell-permeable entiomerically pure compound that is structurally similar to and exhibits similar potency (IC
50 = 63 nM) and selectivity as SIRT1 Inhibitor III (Cat. No.
566322). Shown to be orally bioavailable with a serum half-life of 94 minutes in mice
in vivo.
Biochem/physiol Actions
CHIC-35 is cell-permeable, metabolically stable, and very potent inhibitor of SIRT1; IC50 of S-isomer is 60 nM; IC50 of mixed isomers is 124 nM. There is no inhibition of SIRT3 or HDAC. The IC50 for SIRT2 is 2.77 μM. Sirtuins are protein deacetylases, which represent a new class of histone deacetylases (HDAC) involved in gene silencing. SIRT modulators are potential therapeutics for cancer, diabetes, muscle differentiation, heart failure, neurodegeneration, and aging.
IC 50
SIRT1: 0.124 μM (IC50); SIRT2: 2.8 μM (IC50); SIRT3: >100 μM (IC50)
References
[1] Jér?me Lugrin, et al. The sirtuin inhibitor cambinol impairs MAPK signaling, inhibits inflammatory and innate immune responses and protects from septic shock. Biochim Biophys Acta. 2013 Jun;1833(6):1498-510 DOI:
10.1016/j.bbamcr.2013.03.004[2] Zainab Asad, et al. Chemical screens in a zebrafish model of CHARGE syndrome identifies small molecules that ameliorate disease-like phenotypes in embryo. Eur J Med Genet. 2020 Feb;63(2):103661. DOI:
10.1016/j.ejmg.2019.04.018
