AZ-1

Product NameAZ-1
CAS2165322-94-9
MFC17H16BrF4NO2
MW422.21
EINECS
MOL File2165322-94-9.mol

Chemical Properties

Boiling point	478.5±40.0 °C(Predicted)
Density	1.488±0.06 g/cm3(Predicted)
storage temp.	Store at -20°C
solubility	DMSO: ≥ 250 mg/mL (592.12 mM); Water: < 0.1 mg/mL (insoluble)
pka	14.74±0.10(Predicted)
form	Solid
color	White to off-white
InChI	InChI=1S/C17H16BrF4NO2/c18-13-2-4-16(12(8-13)9-23-5-6-24)25-10-11-1-3-15(19)14(7-11)17(20,21)22/h1-4,7-8,23-24H,5-6,9-10H2
InChIKey	ITHSFXDGKQYOED-UHFFFAOYSA-N
SMILES	C(O)CNCC1=CC(Br)=CC=C1OCC1=CC=C(F)C(C(F)(F)F)=C1

Safety Information

WGK Germany	WGK 3
Storage Class	11 - Combustible Solids

Usage And Synthesis

Uses

USP25/28 inhibitor AZ1 (AZ1) is an orally active, selective, noncompetitive, dual ubiquitin specific protease (USP) 25/28 inhibitor with IC50s of 0.7 μM and 0.6 μM, respectively. USP25/28 inhibitor AZ1 attenuates colitis and tumorigenesis in the mice model[1][2].

Biological Activity

AZ1 is a potent and selective dual USP25 & USP28 deubiquitinase (DUBs) inhibitor (USP25/28 IC50 = 0.62/0.7 nM by Ub-Rh110 assay) th at induces HCT116 cellular c-Myc degradation (20-100 μM for 3h or 60 μM for 0.3-3h). AZ1 exhibits antiproliferation activity in cancer cultures (IC50 ≤20 μM; HCT116, HT29 and SW480) and anti-tumor efficacy in an orthotopic model of lung SCC tumours in mice in vivo (125 mg/kg or 375 mg/kg i.p. once every three days, 6 injections total).

in vivo

USP25/28 inhibitor AZ1 (AZ1; 40mg/kg; gavage; daily; for 7days) protects from dextran sulfate sodium (DSS)-induced weight loss and diarrhea and impaired colon shortening^[1].
USP25/28 inhibitor AZ1 (20mg/kg/day; gavage; 6 times a week in the 1, 3, 6 weeks) treatment significantly reduces tumor numbers in colons. Expression of Wnt-related genes and levels of pSTAT3 are decreased and levels of SOCS3 are increased in tumors. AZ1 gavage does not alleviate DSS-induced colitis in Usp25^-/- mice or the spontaneous colitis of Il10^-/- mice^[1].
USP25/28 inhibitor AZ1 (20mg/kg/day; gavage; every 3days from 13-20 weeks) significantly inhibits tumorigenesis in the colon and prolonged the survival of AOM/Vil-Cre;Trp53^fl/fl (VP) mice. AZ1 treatment has minimal effect on tumorigenesis in the USP25-deficient background^[1].

Animal Model:	12-week old male Usp25^+/+ and Usp25^-/- mice^[1]
Dosage:	40mg/kg
Administration:	Gavage; daily; for 7days
Result:	Protected from dextran sulfate sodium (DSS)-induced weight loss and diarrhea and impaired colon shortening and potentiated the expression of proinflammatory cytokines and antibacterial peptides in colons of Usp25^-/- mice compared to control counterparts.

References

[1] Wrigley JD, et al. Identification and Characterization of Dual Inhibitors of the USP25/28 Deubiquitinating EnzymeSubfamily. ACS Chem Biol. 2017 Dec 15;12(12):3113-3125. DOI:10.1021/acschembio.7b00334
[2] Xiao-Meng Wang, et al. The deubiquitinase USP25 supports colonic inflammation and bacterial infection and promotes colorectal cancer. Nature Cancer volume 1, pages811–825(2020).

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