G-749

Research use only, not for human use.

G-749, a new-type FLT3 inhibitor, exhibits effective and sustained inhibition of the FLT3 wild type and mutants.

G-749 is a novel FLT3 inhibitor that showed potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L in cellular assays. G-749 retained its inhibitory potency in various drug-resistance milieus such as patient plasma, FLT3 ligand surge, and stromal protection. Furthermore, it displayed potent antileukemic activity in bone marrow blasts from AML patients regardless of FLT3 mutation status, including those with little or only minor responses to AC220 or PKC412. Oral administration of G-749 yielded complete tumor regression and increased life span in animal models. Thus, G-749 appears to be a promising next-generation drug candidate for the treatment of relapsed and refractory AML patients with various FLT3-ITD/FLT3-TKD mutants and further shows the ability to overcome drug resistance.

Denfivontinib shows potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L in cellular assays.Denfivontinib inhibits autophosphorylation of FLT3 with an IC50 value of ≤8 nM in FLT3-WT bearing RS4-11 and in FLT3-ITD harboring MV4-11 and Molm-14 cells.Denfivontinib (0.0001-10 nM; 72 hours) shows strong antiproliferation of leukemia cells addicted to FLT3-ITD (MV4-11 and Molm-14) in a dose-dependent manner.Denfivontinib (25-100 nM; 36 hours) causes antiproliferative activity through apoptosis.Denfivontinib (1.6-1000 nM; 2 hours) shows more potent inhibition of p-FLT3, p-ERK1/2, and p-AKT than AC220 and PKC412. Cell Proliferation Assay Cell Line:MV4-11 cells, Molm-14 cells, K562 cells, HEL cells, RS4-11 cellsConcentration:0.0001-10 nM Incubation Time:72 hours Result:Had antiproliferative activity for leukemia cells addicted to FLT3-ITD.Apoptosis Analysis Cell Line:MV4-11 cells Concentration:25 nM, 50 nM, 100 nM Incubation Time:36 hours Result:Increased apoptosis of MV4-11 cells in a dose-dependent manner.Western Blot Analysis Cell Line:Molm-14 cells Concentration:1.6 nM, 80 nM, 40 nM, 200 nM, 1000 nMIncubation Time:2 hours Result:Inhibited the phosphorylation of downstream effectors in the FLT3 signaling pathway, such as p-STAT5, p-AKT, p-ERK1/2, and p-FoxO3a.

Denfivontinib (3-30 mg/kg; p.o.; daily; for 28 days) shows effective antitumor activity in mouse models. Animal Model:Athymic nu/nu mice, subcutaneous MV4-11 xenograft mice Dosage:3 mg/kg, 10 mg/kg, 30 mg/kg Administration:Oral administration, daily, for 28 days Result:Suppressed tumor growth.

alpha-MCPG

Metabolic Enzyme/Protease

Dehydrogenase

Aurora B| RET| FLT3| FLT3 (D835Y)| Mer

Cancer

——

1457983-28-6

521.41

C25H25BrN6O2

>98% (HPLC)

DMSO : 25 mg/mL; 47.95 mM;

CN1CCC(CC1)NC1=NC2=C(C(=O)NC=C2Br)C(NC2=CC=C(OC3=CC=CC=C3)C=C2)=N1

8-bromo-2-((1-methylpiperidin-4-yl)amino)-4-((4-phenoxyphenyl)amino)pyrido[4,3-d]pyrimidin-5(6H)-one

(-20℃)

With Ice Pack

≥ 2 years