Dovitinib

SKU: orb1941045

Description

A novel, multitargeted RTK inhibitor of class III, IV, and V RTKs with IC50 of 1/2/36/8/9 nM for FLT3/c-KIT/c-Fms/FGFR1/FGFR3, respectively; also inhibits VEGFR1/2/3 (IC50=10/13/8 nM) and PDGFRβ/α (IC50=27/210 nM); selectively inhibits the growth of B9 cells and human myeloma cell lines expressing wild-type (WT) or activated mutant FGFR3; inhibits downstream ERK 1/2 phosphorylation and induces cytostatic and cytotoxic effects; demonstrates activity in a xenograft mouse model of FGFR3 MM; orally active.Blood Cancer Phase 2 Clinical(In Vitro):Dovitinib (CHIR-258) shows more than 10-fold inhibition InsR (IC50=2 μM), EGFR1 (IC50=2 μM), c-Met (IC50>3 μM), EphrinA2 (EphA2; IC50=4 μM), Tie2 (IC50=4 μM), IGFR1 (IC50>10 μM), and HER2 (IC50>10 μM).Dovitinib (12.5-400 nM; 48 hours) potently inhibits the FGF-stimulated growth of WT and F384L-FGFR3-expressing B9 cells with IC50 values of 25 nM.Dovitinib (100, 500 nM; 96 hours) inhibits FGF-mediated ERK1/2 phosphorylation and induces apoptosis of FGFR3-expressing human myeloma cell lines.Dovitinib (72 hours) inhibits cell proliferation of KMS11 (FGFR3-Y373C), OPM2 (FGFR3-K650E), and KMS18 (FGFR3-G384D) cells with IC50 of values of 90 nM (KMS11 and OPM2) and 550 nM, respectively.Dovitinib (100 nM) augments Dexamethasone (0.5 μM) cytotoxicity in KMS11 cells.Dovitinib significantly reduces the basal phosphorylation levels of FGFR-1, FGFR substrate 2α (FRS2-α) and ERK1/2 but not Akt in both SK-HEP1 and 21-0208 cells.Dovitinib enhances the BMP-2-induced alkaline phosphatase (ALP) induction, which is a representative marker of osteoblast differentiation. Dovitinib also stimulates the translocation of phosphorylated Smad1/5/8 into the nucleus and phosphorylation of mitogen-activated protein kinases, including ERK1/2 and p38.Dovitinib strongly inhibits both the interaction of TNIK with ATP (Ki, 13 nM) and the activation of Wnt signaling effectors such as β-catenin and TCF4. Dovitinib also induces caspase-dependent apoptosis in IM-9 cells without significant cytotoxicity in PBMCs.(In Vivo):Dovitinib (CHIR-258; 10-60 mg/kg/day; gavage; for 21 days) has a significant antitumor effect.Dovitinib (50 and 75 mg/kg) results in 97% and 98% tumor growth inhibition, respectively, and the maximal efficacy is at 50 mg/kg.

Key Properties

• CAS Number: 405169-16-6
• MW: 392.4294
• Purity: >98% (HPLC)
• Formula: C₂₁H₂₁FN₆O
• SMILES: CN1CCN(CC1)C2=CC3=C(C=C2)N/C(=C/4\C(=C5C(=NC4=O)C=CC=C5F)N)/N3
• Target: FGFR
• Solubility: DMSO: 25 mg/mL

Bioactivity

• In Vivo:
  Dovitinib (CHIR-258; 10-60 mg/kg/day; gavage; for 21 days) has a significant antitumor effect. Dovitinib (50 and 75 mg/kg) results in 97% and 98% tumor growth inhibition, respectively, and the maximal efficacy is at 50 mg/kg. Animal model: 6-to 8-week-old female BNX mice with KMS11 cells. Dosage: 10, 30, 60 mg/kg. Administration: Gavage; daily for 21 days. Result: Had a significant antitumor effect in all 3 dose groups with 48%, 78.5%, and 94% growth inhibition in the 10 mg/kg, 30 mg/kg, and 60 mg/kg treatment.
• In Vitro:
  Dovitinib (CHIR-258) shows more than 10-fold inhibition InsR (IC50 = 2 μM), EGFR1 (IC50 = 2 μM), c-Met (IC50>3 μM), EphrinA2 (EphA2; IC50 = 4 μM), Tie2 (IC50 = 4 μM), IGFR1 (IC50>10 μM), and HER2 (IC50>10 μM). Dovitinib (12.5-400 nM; 48 hours) potently inhibits the FGF-stimulated growth of WT and F384 L-FGFR3-expressing B9 cells with IC50 values of 25 nM. Dovitinib (100, 500 nM; 96 hours) inhibits FGF-mediated ERK1/2 phosphorylation and induces apoptosis of FGFR3-expressing human myeloma cell lines. Dovitinib (72 hours) inhibits cell proliferation of KMS11 (FGFR3-Y373C), OPM2 (FGFR3-K650E), and KMS18 (FGFR3-G384D) cells with IC50 of values of 90 nM (KMS11 and OPM2) and 550 nM, respectively. Dovitinib (100 nM) augments Dexamethasone (0.5 μM) cytotoxicity in KMS11 cells. Dovitinib significantly reduces the basal phosphorylation levels of FGFR-1, FGFR substrate 2α (FRS2-α) and ERK1/2 but not Akt in both SK-HEP1 and 21-0208 cells. Dovitinib enhances the BMP-2-induced alkaline phosphatase (ALP) induction, which is a representative marker of osteoblast differentiation. Dovitinib also stimulates the translocation of phosphorylated Smad1/5/8 into the nucleus and phosphorylation of mitogen-activated protein kinases, including ERK1/2 and p38.Dovitinib strongly inhibits both the interaction of TNIK with ATP (Ki, 13 nM) and the activation of Wnt signaling effectors such as β-catenin and TCF4. Dovitinib also induces caspase-dependent apoptosis in IM-9 cells without significant cytotoxicity in PBMCs. Cell Viability Assay Cell line: WT and F384 L-FGFR3-expressing B9 cells. Concentration: 12.5, 25, 50, 100, 200, 300, 400 nM Incubation time: 48 hours. Result: Potently inhibited the FGF-stimulated growth of the cells. Apoptosis Analysis Cell line: KMS11, OPM2, and KMS18 cells. Concentration: 100 nM or 500 nM. Incubation time: 96 hours. Result: Induced apoptosis of FGFR3-expressing human myeloma cell lines.

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

CHIR-258 | TKI258 | TKI-258 | TKI 258 | CHIR258 | CHIR 258

Quick Database Links

Gene Symbol

FGFR