CYP51/HDAC-IN-1

CYP51/HDAC-IN-1 is a potent, orally active CYP51/HDAC dual inhibitor. CYP51/HDAC-IN-1 inhibits important virulence factors and down-regulated resistance-associated genes. CYP51/HDAC-IN-1 exhibits potent therapeutic effects for both tropical candidiasis and cryptococcal meningitis[1].

Signaling Pathways >> Metabolic Enzyme/Protease >> Cytochrome P450

Signaling Pathways >> Anti-infection >> Fungal

Research Areas >> Inflammation/Immunology

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

Signaling Pathways >> Epigenetics >> HDAC

CYP51

CYP51/HDAC-IN-1 (compound A5) exhibits the best inhibitory activity against both Candida tropicalis (C. tropicalis) and Cryptococcus neoformans (C. neoformans) with an MIC80 of 0.5 µg/mL[1]. CYP51/HDAC-IN-1 (human umbilical vein endothelial cell line (HUVEC)) shows low toxicity to human normal cells (IC50= 5.9 µg/mL (10.36 µM))[1]. CYP51/HDAC-IN-1 inhibits biofilm formation of C. tropicalis and C. neoformans in a dose-dependent manner[1]. CYP51/HDAC-IN-1 reduces the virulence of C. neoformans through down-regulating capsule-associated genes CAP10 and CAP60[1]. CYP51/HDAC-IN-1 increases the activity against FLC-resistant C. tropicalis by inhibits the overexpression of efflux pump genes, and down-regulated ERG11 gene in ergosterol biosynthetic pathway[1]. CYP51/HDAC-IN-1 exhibits HDAC inhibitory activity (IC50=2.38 µM) and down-regulated HDAC genes (Rpd3, Hos1, Hos2, Clr61, Clr62, Hda1 and Hos3)[1].

CYP51/HDAC-IN-1 (20 mg/kg; p.o.; once a day for 5 consecutive days) exhibits potent therapeutic effects for both tropical candidiasis and cryptococcal meningitis (CM)[1]. Animal Model: Female ICR mice, 4-6 weeks, 18-20g (injection with C. tropicalis and C. neoformansvia tail vein)[1] Dosage: 20 mg/kg Administration: p.o.; once a day; 5 consecutive days Result: Reduced kidney fungal burden and brain fungal burden.

[1]. Zhu T, et al. Lanosterol 14α-demethylase (CYP51)/histone deacetylase (HDAC) dual inhibitors for treatment of Candida tropicalis and Cryptococcus neoformans infections. Eur J Med Chem. 2021. 221:113524.