G-749

SKU: orb1223292

Description

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.

Key Properties

• CAS Number: 1457983-28-6
• MW: 521.41
• Purity: >98% (HPLC)
• Formula: C₂₅H₂₅BrN₆O₂
• SMILES: CN1CCC(CC1)NC1=NC2=C(C(=O)NC=C2Br)C(NC2=CC=C(OC3=CC=CC=C3)C=C2)=N1
• Target: Dehydrogenase
• Solubility: DMSO : 25 mg/mL; 47.95 mM

Bioactivity

• In Vivo:
  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.
• In Vitro:
  Denfivontinib shows potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691 L 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 cells. Concentration: 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 nM Incubation 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.

Storage & Handling

• Storage: Storage temperature: -20°C. Stability: ≥ 2 years
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

alpha-MCPG

Quick Database Links

Gene Symbol

Dehydrogenase