JPC0661

JPC0661 is a direct and allosteric ΔFOSB inhibitor. JPC0661 inhibits the binding of ΔFOSB /JUND and ΔFOsB to DNA with IC₅₀ values in the micromolar range (9-52 uM), directly inhibits ΔFOSB -mediated transcription with IC₅₀ of 0.82 μM in vitro. JPC0661 significantly reduces ΔFOSB occupancy at genomic AP1 sites in vivo. JPC0661 binds to a novel groove outside the DNA-binding cleft of ΔFOSB and disrupt the formation of the ΔFOSB /JUND-DNA complex. JPC0661 can be used for Alzheimer's disease research ^[1].

In Vivo, JPC0661 (50 μM, 16.7 ng/h, intra-hippocampal infusion, for 3 days ) causes a robust, broad reduction in ΔFOSB binding across most this transcription factor’s normal genomic locations in heterozygous transgenic male and female mice expressing human amyloid precursor protein (APP) carrying Swedish (K670N, M671L) and Indiana (V717F) mutations^[1].

In Vitro, JPC0661 (0-100 μM) regulate ΔFOSB-driven gene expression with IC₅₀ of 0.82 μM and accumulates ΔFOSB protein in HEK293 cells^[1]. JPC0661 (0-100 μM, 24 or 72 h) has good tolerance in neuronal progenitor cells, AP1-luc HEK293 cells and d Neuro2A cells (NPC) ^[1].

References:
[1]. McNeme S, et al. Discovery of Small Molecules and a Druggable Groove That Regulate DNA Binding and Release of the AP-1 Transcription Factor ΔFOSB. J Biol Chem. 2025 Dec 22:111080.