| 描述 | UNC2025 hydrochloride is a potent, ATP-competitive, highly orally active Mer/Flt3 inhibitor. It has IC50 values of 0.74 nM and 0.8 nM, respectively, for Mer and Flt3. UNC2025 hydrochloride demonstrates over 45-fold selectivity for MERTK compared to Axl (IC50 = 122 nM; Ki = 13.3 nM). Additionally, UNC2025 hydrochloride exhibits excellent PK properties, making it suitable for investigating acute leukemia. |
| 体外活性 | UNC2025 is against FLT3, MER, AXL, TRKA, TRKC, QIK, TYRO3, SLK, NuaK1, KIT and Met with IC 50 values of 0.35 nM, 0.46 nM, 1.65 nM, 1.67 nM, 4.38 nM, 5.75 nM, 5.83 nM, 6.14 nM, 7.97 nM , 8.18 nM and 364 nM, respectively[1].
UNC2025 (0-60 nM; 1 hour) mediates potent inhibition of Mer phosphorylation with an IC 50 of 2.7 nM?in 697 B-ALL cells[1].
UNC2025 (0-60 nM; 1 hour) results in decreased phosphorylation of Flt3 with an IC 50 of 14 nM in Flt3-ITD positive Molm-14 acute myeloid leukemia cells[1].UNC2025 (3 nM-3 μM; 1 hour) decreases p-MEK, p-AXL, p-TYRO3 expression as a concentration manner in 32D Cells[1].
UNC2025 (14 nM–10 μM; 48 hours) inhibits MERTK signaling and colony-forming potential in a MERTK-expressing patient sample with a 20-fold difference in sensitivity of MERTK-expressing leukemia blasts relative to normal cord or marrow blood mononuclear cells[2].UNC2025 (25-300 nM; 1 hour) mediates potent and dose-dependent decreases in MERTK phosphorylation/activation in both cell lines and inhibition of MERTK correlated with decreased phosphorylation of previously reported MERTK-dependent signaling components STAT6, AKT, and ERK1/2[2]. Western Blot Analysis[1]Cell Line: 32D Cells Concentration: 0 nM, 3 nM, 10 nM, 20 nM, 30 nM, 100 nM, 1000 nM, 3000 nM Incubation Time: 1 hour Result: Inhibited p-MEK, p-AXL, p-TYRO3 expression. Cell Proliferation Assay[1]Cell Line: Mononuclear cells Concentration: 14 nM–10 μM Incubation Time: 48 hours Result: Showed IC 50 values ranged from 9.0 nM to >10 μM with a median IC 50 of 2.38 μM. Western Blot Analysis[2]Cell Line: Kasumi-1 AML and 697 B-ALL cells Concentration: 25-300 nM Incubation Time: 48 hours Result: Decresed p-MERTK, p-STAT6, p- AKT and p-ERK1/2 expression as a dose-dependent manner. |
| 体内活性 | UNC2025 (intravenous injection or oral adminstration; 3 mg/kg) exhibits an excellent PK properties: low clearance (9.2 mL/min kg), longer half-life (3.8 h), and high oral exposure (100%), it shows T max , C max , and AUClast 0.50 hour, 1.6 μM, and 9.2 h?μM, respectively[2].
UNC2025 (orally adminstration; 50 or 75 mg/kg; 34 and 70 days) mediates a statistically significant dose-dependent reduction in tumor burden relative to vehicle. mediates dose-dependent increases in median survival from 26 days after initiation of treatment in vehicle-treated mice, to 34 and 70 days in mice treated with 50 or 75 mg/kg UNC2025, respectively[2]. Animal Model: NSG mice injected with 697 B-ALL cells[2]Dosage: 50 or 75 mg/kg Administration: Oral adminstration Result: Delayed the disease progression. |