(S)-2-chloro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-6-carboxamide

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].

Signaling Pathways >> Epigenetics >> Sirtuin

Signaling Pathways >> Cell Cycle/DNA Damage >> Sirtuin

Research Areas >> Inflammation/Immunology

Research Areas >> Neurological Disease

SIRT1:0.124 μM (IC50)

SIRT2:2.8 μM (IC50)

SIRT3:>100 μM (IC50)

CHIC-35 (0.5 μM; 16 hours) increases acetylation of histone H4 in BMDMs similar to Cambinol (200 μM)[1]. CHIC-35 (5 μM; 72 hours) exhibits no significant difference in the survival of embryos at early stages[2]. Zebrafish embryos are microinjected with 2.4 ng of chd7 MO to develop to different stages of development. chd7 morphant embryos are treated with CHIC-35 from 8hpf to 24hpf. CHIC-35 (5 μM) is removed at 24hpf and embryos are incubated in fresh egg water until 4dpf. The chd7 morphant larvae has a severely reduced and disrupted pattern of cartilage elements in comparison to the control, CHIC-35 shows partial recovery in craniofacial cartilage elements[2]. At 4dpf, zebrafish embryos show a well-formed lower jaw in controls, while chd7 morphants exhibits reduced lower jaw. Treatment with CHIC-35 (5 μM) rescues the expression of sox9a inchd7 morphants[2]. Nearly 30% of chd7 morphant embryos (24hpf to 72hpf) shows a near complete loss of isl2a expression in the cranial region compared to 10% of the wildtype controls. CHIC-35 reduces this to 7.5% significantly. However, CHIC-35 shows no discernible effect on the enteric neurons marked by Tg[2].

[1]. Jérôme 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

[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.