QNZ | NFkB inhibitor / Store operated calcium entry

QNZ (545380-34-5) was originally described as a potent inhibitor of NF-κB activation (IC₅₀ = 11 nM) and TNF-α production (IC₅₀ = 7 nM).^1,2 It indirectly inhibits the NF-κB pathway via inhibition of store-operated calcium entry (SOC) and displayed neuroprotective effects in transgenic fly and mouse models of Huntington’s disease.^3,4 Its target has been postulated to be heteromeric calcium channels containing TRPC1 as one of the subunits.⁴ QNZ reduced synaptic neuronal SOC and rescued dendritic spine loss in YAC128 striatal medium spiny neurons.⁵ QNZ has also been identified as a potent (IC₅₀ = 25 nM complex 1 from Y.lipolytica; IC₅₀ = 14 nM complex 1 from Bos Taurus heart mitochondria) and selective inhibitor of mitochondrial complex I.⁶ QNZ decreased PSEN1ΔE9-mediated nSOCE upregulation and rescued mushroom spines in PSEN1ΔE9-expressing neurons, which are linked to familial Alzheimer’s disease.⁷

References/Citations:

1) Tobe et al. (2003), Discovery of quinazolines as a novel structural class of potent inhibitors of NF-kappa B activation; Bioorg. Med. Chem. Lett, 11 383
2) Tobe et al. (2003), A novel structural class of potent inhibitors of NF-kB activation: structure-activity relationships and biological effects of 6-aminoquinazoline derivatives; Bioorg. Med. Chem. Lett, 11 3869
3) Choi et al. (2006), Nuclear factor-kappaB activated by capacitive Ca2+ entry enhances muscarinic receptor-mediated soluble amyloid precursor protein (sAPPalpha) release in SH-SY5Y cells; J. Biol. Chem., 281 12722
4) Wu et al. (2011), Neuronal Store-Operated Calcium Entry Pathway as a Novel Therapeutic Target for Huntington’s Disease Treatment; Chem. Biol., 18 777
5) Wu et al. (2016), Enhanced Store-Operated Calcium Entry Leads to Striatal Synaptic Loss in a Huntington’s Disease Mouse Model; J. Neurosci., 36 125
6) Krishnathas et al. (2017), Identification of 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine as a novel, highly potent and specific inhibitor of mitochondrial complex I; Medchemcomm. 8 657
7) Chernyuk et al. (2019), Antagonist of neuronal store-operated calcium entry exerts beneficial effects in neurons expressing PSEN1∆E9 mutant linked to familial Alzheimer disease; Neuroscience, 410 118