The bone morphogenetic protein (BMP) signal transduction pathway is a subset of the larger TGF-β signaling family, which includes 7 type I receptors, 5 type II receptors, and over 30 ligands of the BMP, TGF-β, activin, and growth and differentiation factor (GDF) ligand families[2]. LDN-214117 is a high degree of selectivity inhibitor for the BMP type I receptor kinase ALK2 with IC50 value of 24 nM. LDN-214117 also inhibits the activity of BMP6 and TGFβ with IC50 values of 67 nM and 14.65 μM, respectively (measured by ligand induced transcriptional assay)[1]. In vitro, LDN-214117 inhibited ACR1 wild-type cells SU-DIPG-VI and QCTB-R059 with GI50 values of 5.38 μM and 8.27 μM, respectively. LDN-214117 also inhibited cell viability of the ACVR1 mutant cells HSJD-DIPG-007(R206H), SU-DIPG-IV(G238V) and HSJD-DIPG-018(R258G) with GI50 values of 1.57 μM, 6.23 μM and 16.38 μM, respectively. Treatment DIPG cell lines SU-DIPG-VI and HSJD-DIPG-IV with 0.1 μM LDN-214117 for 4h inhibited phosphor-SMAD1/5/8 and the downstream effector ID1[3]. In addition, treatment the lung carcinoma cell line LCLC-103H with LDN-214117 at concentration of 5 μM significantly hindered the migration of LCLC-103H cells into the wound area, reaching relative wound density of only 50% in 48h by inhibition of BMP signaling[4]. In vivo, the bioavailability (F) and well-tolerance level of LDN-214117 was 0.75 and 25 mg/kg, respectively. Oral administration of LD-214117 at 25 mg/kg for 28 days extended survival in immunodeprived mice bearing orthotopic xenografts of H3.3K27M, ACVR1R206H mutant HSJDDIPG-007 cells[3].
LDN-214117 细胞实验
Cell Line
Concentration
Treated Time
Description
References
QCTB-R059 cells
8.27 µM
8 days
Evaluate the inhibitory effect of LDN-214117 on ACVR1 wild-type DIPG cells, showing a GI50 of 8.27 µM.
Commun Biol. 2019 May 9;2:156.
SU-DIPG-VI cells
5.83 µM
8 days
Evaluate the inhibitory effect of LDN-214117 on ACVR1 wild-type DIPG cells, showing a GI50 of 5.83 µM.
Commun Biol. 2019 May 9;2:156.
SU-DIPG-IV cells
6.23 µM
8 days
Evaluate the inhibitory effect of LDN-214117 on ACVR1 G328V mutant DIPG cells, showing a GI50 of 6.23 µM.
Commun Biol. 2019 May 9;2:156.
HSJD-DIPG-007 cells
1.57 µM
8 days
Evaluate the inhibitory effect of LDN-214117 on ACVR1 R206H mutant DIPG cells, showing a GI50 of 1.57 µM.
Commun Biol. 2019 May 9;2:156.
HepG2 cells
1, 10, 100 μM
4 and 24 hours
Evaluate the cytotoxicity of LDN-214117, showing low cytotoxicity.
J Med Chem. 2014 Oct 9;57(19):7900-15.
HEK293T cells
1 nM to 10 μM
Overnight
Evaluate the inhibitory effect of LDN-214117 on TGF-β1-induced transcriptional activity, IC50 approximately 16.4 μM.
J Med Chem. 2014 Oct 9;57(19):7900-15.
C2C12 cells
1 nM to 10 μM
Overnight
Evaluate the inhibitory effect of LDN-214117 on BMP6-induced transcriptional activity, IC50 approximately 100 nM.
J Med Chem. 2014 Oct 9;57(19):7900-15.
HUVECs
20 μM
24 hours
LDN-214117 significantly increased the intercellular exchange efficacy of T-AgNPs and R-AgNPs from HUVEC to PC3-GFP cells
Adv Ther (Weinh). 2023 Feb;6(2):2200173.
PC-3 cells
20 μM
24 hours
LDN-214117 significantly increased the intercellular exchange efficacy of T-AgNPs and R-AgNPs
Adv Ther (Weinh). 2023 Feb;6(2):2200173.
C2C12 cells
21nM-10μM
30 minutes
To distinguish ALK2 ligand-mediated signaling from ALK3 and ALK1 ligand-mediated signaling
Methods Mol Biol. 2019;1891:221-233.
LDN-214117 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NOD.SCID mice
HSJD-DIPG-007 orthotopic xenograft model
Oral
25 mg/kg
Daily administration for 28 days
Evaluate the therapeutic effect of LDN-214117 in ACVR1 R206H mutant DIPG model, showing significantly extended survival compared to controls (75 days vs 61 days).
Commun Biol. 2019 May 9;2:156.
Balb/c mice
4T1 breast tumor model
Intratumoral injection
200 μM (20 μL)
Once daily for 5 days
LDN-214117 significantly increased the accumulation and vascular penetration distance of iRGD-Liposome and iRGD-AgNPs in tumor tissue
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