AZ084

AZ084 is a potent, selective, allosteric and oral active CCR8 allosteric antagonist, with a K i of 0.9 nM. Has potential to treat asthma AZ084 restrains the formation of the immunologically tolerant pre-metastatic niche (PMN) and tumor cells metastasis in lung by downregulating Treg differentiation. AZ084 can be used in studies of asthma and cancer

In Vitro

AZ084 (5 μg/mL; single daily for 4 days) suppresses proportion of Tregs and reduces T cells that expresses CCR8 (co-cultured in vitro with LLC-exo MPF CM). ?\nAZ084 (0-10 μM) inhibits AML, DC and T cells with IC 50 s of 1.3, 4.6 and 5.7 nM, respectively. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Viability AssayCell Line: Splenic T cells Concentration: 5 μg/mL (single daily) Incubation Time: 4 days Result: Reversed the increased proportion of Tregs among the CD4+ T cells co-cultured in vitro with LLC-exo MPF CM. Reduced T cells that expressed CCR8 (cultured in vitro with by LLC-exo MPF CM). Cell Viability AssayCell Line: AML, DC and T cells Concentration: 0-10 µM Incubation Time: Result: Showed high potency with pronounced dose-response dependent inhibition of chemotaxis with an IC 50 of 1.3 nM in AML cells.

In Vivo

AZ084 (5 mg/kg; i.p.; every third day for 9 or 21 days) restrains the formation of the immunologically tolerant PMN and tumor cells metastasis in lung by downregulating Treg differentiation . ?\nAZ084 (434.57-869.14 mg/kg; i.v.; single) shows a bioavailability >70% in rats. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: C57BL/6 J mice (subcutaneous LLC tumor model) . Dosage: 5 mg/kg Administration: Intraperitoneal injection, every third day for 9 or 21 days. Result: Inhibited Treg differentiation and tumor cell colonization of the lungs and reduced the number of CD4+Foxp3+ Tregs in the lungs of LLC-exo pre-injected mice (every third day for 9 days). Inhibited the LLC-exo-induced LLC cell seeding in lung and also significantly reduced Treg accumulation in LLC-exo stimulated mouse lungs(every third day for 21 days). Animal Model: Female Balb/C mice, male Wistar rats and female Beagle dogs. Dosage: 434.57-869.14 mg/kg (in 0.9% NaCl) Administration: Intravenous injection, single. Result: 1.19 Pharmacokinetic Parameters of AZ084 in Female Balb/C mice, male Wistar rats and female Beagle dogs. IV (434.57-869.14 mg/kg) Dog plasma protein binding (% free) 45.7 Mu plasma protein binding (% free) 55.6 Hu plasma protein binding (% free) 31.0 Rat plasma protein binding (% free) 47.0 Rat HW plasma PK CL (mL/min/kg) 15.0 Rat HW plasma PK V ss (L/kg) 6.0 Rat HW plasma PK T 1/2 (h) 5.4 Rat HW plasma PK C max (µM) 0.5 Rat HW plasma PK bioavailability (%) 68.0

IC50& Target:CCR8 0.9 nM (Ki)