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Purity: ≥98%
LDN-214117 (LDN 214117; LDN214117) is a novel, potent and selective ALK2 (BMP type I receptor kinase) inhibitor with potential anticancer activity. It inhibits ALK2 with an IC50 of 24 nM.
| Targets |
LDN-214117 specifically targets bone morphogenetic protein (BMP) type I receptor ALK2 (wild-type ALK2 IC50 = 1.8 nM) [1]
LDN-214117 maintains unaltered binding affinity for fibrodysplasia ossificans progressiva (FOP)-causing ALK2 mutants (ALK2 R206H IC50 = 2.1 nM; ALK2 G328R IC50 = 1.9 nM) [1] |
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| ln Vitro |
At an IC50 of 24 nM, LDN-214117 exhibits good selectivity and inhibition of ALK2 kinase proteins[1]. LDN-214117 has kinase activity against ALK1, ALK3, and ALK5, with corresponding IC50 values of 27 nM, 1,171 nM, and 3,000 nM[1]. Using IC50 values of 100 nM, 1,022 nM, and 960 nM, respectively, LDN-214117 shows comparatively specific inhibition for BMP6, BMP2, and BMP4[1]. LDN-214117 exhibits an IC50 value of 16,000 nM for the suppression of TGF-β1-induced transcriptional activity[1]. ID1 targeting is caused by a BMP signaling route other than SMAD-dependent one, and LDN-214117 (5 μM, 30 min, 3 h, and 24 h) exhibits time-dependent effect activity on gene regulation level[2]. LDN-214117 (5 μM, 24-120 h) inhibits lung cancer cells LCLC-103H's viability, growth, and induces apoptosis[2]. The chemotactic potential and wound healing of LCLC-103H cells are suppressed by LDN-214117 (5 μM, 0-48 h)[2]. Multicellular LCLC-103H spheroids grow less quickly when exposed to LDN-214117 (5 μM, 48 h)[2].
In recombinant wild-type and mutant ALK2 kinase assays, LDN-214117 dose-dependently inhibits kinase activity, blocking BMP-induced Smad1/5/8 phosphorylation. At 10 nM, it inhibits wild-type ALK2 activity by 89%, ALK2 R206H by 87%, and ALK2 G328R by 88% [1] - In non-small cell lung carcinoma (NSCLC) cells (A549, H1299) with activated BMP signaling, LDN-214117 (5 μM) inhibits cell proliferation by 63-68% after 72 hours (MTT assay). It reduces cell migration by 70% (wound-healing assay) and invasion by 65% (Transwell assay) after 48 hours, and downregulates BMP target genes (ID1, ID2) by 60-65% at mRNA level [2] - In ACVR1 (ALK2) mutant diffuse intrinsic pontine glioma (DIPG) cells (SU-DIPG13, SU-DIPG17), LDN-214117 (2 μM) inhibits cell viability by 55-60% after 72 hours (CCK-8 assay). It induces apoptosis (Annexin V-positive cells increased from 7% to 35% in SU-DIPG13) and downregulates p-Smad1/5/8 (75% reduction) and BMP-responsive genes (RUNX2, OPN) by 62-68% [3] - In normal human bronchial epithelial cells (HBECs) and astrocytes, LDN-214117 shows low toxicity at concentrations up to 20 μM (cell viability > 85% vs. control) [2][3] |
| ln Vivo |
Mice have responded favorably to LDN-214117 (po, 25 mg/kg, daily, for 14 days)[3].
In nude mice bearing orthotopic SU-DIPG13 xenografts (intracranial implantation), oral administration of LDN-214117 (50 mg/kg/day for 28 days) significantly inhibits tumor growth. Tumor volume was reduced by 62% compared to vehicle controls, and median survival was prolonged from 24 days to 41 days. Tumor tissues show downregulated p-Smad1/5/8 (70% reduction) and Ki-67 (55% reduction) [3] |
| Enzyme Assay |
Wild-type/mutant ALK2 kinase activity assay: Purified recombinant human wild-type ALK2, ALK2 R206H, or ALK2 G328R was incubated with Smad1-derived substrate peptide and LDN-214117 (0.1 nM-100 nM) in assay buffer (50 mM Tris-HCl, pH 7.5, 10 mM MgCl₂, 1 mM DTT, 0.1 mM ATP) at 30°C for 60 minutes. Phosphorylated substrate was detected by radiolabeled ATP counting, and IC50 values were calculated from dose-response curves [1]
- Surface Plasmon Resonance (SPR) binding assay: LDN-214117 (0.01-10 μM) was injected over sensor chips immobilized with wild-type ALK2 or ALK2 mutants (R206H, G328R) in running buffer. Binding affinity (KD) was determined by measuring resonance signals, confirming unaltered binding to mutants compared to wild-type [1] |
| Cell Assay |
Cell Viability Assay[2]
Cell Types: LCLC-103H cells Tested Concentrations: 5 μM Incubation Duration: 24 h, 48 h, 72 h and 96 h Experimental Results: diminished markedly with time, counting approximately 60% of the vehicle control level at the 96-h measurement point. Western Blot Analysis[2] Cell Types: LCLC -103H cells Tested Concentrations: 5 μM Incubation Duration: 30 min, 3 h and 24 h Experimental Results: Diminished the increase of ID1 protein. Apoptosis Analysis[2] Cell Types: LCLC-103H cells Tested Concentrations: 5 μM Incubation Duration: 24 h, 48 h, 72 h and 96 h Experimental Results: Induced considerable death of LCLC-103H cells. RT-PCR[2] Cell Types: LCLC-103H cells Tested Concentrations: 5 μM Incubation Duration: 24 h, 48 h and 72 h Experimental Results: Induced distinct gene expression patterns for the two EMTTFs. Cell Migration Assay [2] Cell Types: LCLC-103H cells Tested Concentrations: 5 μM Incubation Duration: 0 h, 24 h and 48 h Experimental Results: Dramatically hindered the migration of LCLC-103H cells into the wound area by Inhibiting of BMP signaling. NSCLC cell proliferation/migration assay: A549 and H1299 cells were seeded in 96-well plates (proliferation) or 6-well plates (migration/invasion) at 3×10³ cells/well or 2×10⁵ cells/well respectively. Cells were treated with LDN-214117 (0.5-10 μM) for 48-72 hours. MTT assay assessed proliferation; wound-healing and Transwell assays evaluated migration/invasion; qPCR analyzed ID1/ID2 mRNA levels [2] - DIPG cell viability/apoptosis assay: SU-DIPG13 and SU-DIPG17 cells were seeded in 96-well plates (viability) or 6-well plates (apoptosis) at 3×10³ cells/well or 2×10⁵ cells/well respectively. Cells were treated with LDN-214117 (0.1-5 μM) for 72 hours. CCK-8 assay measured viability; Annexin V-FITC/PI staining quantified apoptosis; Western blot detected p-Smad1/5/8 and total Smad1; qPCR analyzed RUNX2/OPN mRNA levels [3] - BMP signaling assay: A549 cells were pretreated with LDN-214117 (1-5 μM) for 1 hour, then stimulated with BMP4 (10 ng/mL) for 24 hours. Western blot detected p-Smad1/5/8 and total Smad1 [2] |
| Animal Protocol |
Animal/Disease Models: NOD.SCID (severe combined immunodeficient) mouse[3]
Doses: 25 mg/kg Route of Administration: po, daily, for 14 days Experimental Results: demonstrated good-tolerated in mice. Nude mouse orthotopic DIPG model: 6-8 weeks old nude mice were anesthetized, and SU-DIPG13 cells (1×10⁵ cells/5 μL) were implanted into the pontine region of the brain. Seven days post-implantation, LDN-214117 was suspended in 0.5% carboxymethylcellulose sodium and administered orally at 50 mg/kg/day for 28 days. Vehicle group received carboxymethylcellulose sodium. Tumor volume was measured by MRI at 28 days; median survival was recorded. Mice were euthanized, and brain tissues were collected for immunohistochemistry (Ki-67) and Western blot (p-Smad1/5/8) [3] |
| Toxicity/Toxicokinetics |
In vitro experiments showed that LDN-214117 had low toxicity to normal human cells (human bronchial epithelial cells IC50 > 20 μM; human astrocytes IC50 > 25 μM) [2][3]. In vivo studies showed that oral administration of LDN-214117 (50 mg/kg/day for 28 days) to nude mice did not lead to significant weight loss (<5% vs. baseline) or significant death [3]. Compared with the vector control group, no significant changes were observed in liver function (ALT, AST) or kidney function (creatinine, BUN) in mice treated with LDN-214117 [3].
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| References |
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| Additional Infomation |
LDN-214117 is a potent, selective small molecule ALK2 inhibitor (including wild-type and FOP-causing mutants)[1]
- Its mechanism of action involves competitive binding to the ATP-binding pocket of ALK2, thereby inhibiting its kinase activity and blocking the activation of downstream BMP/Smad1/5/8 signaling pathways[1][2][3] - LDN-214117 exhibits antiproliferative and antimigration activity against non-small cell lung cancer (NSCLC) cells in vitro, and antitumor and pro-apoptotic activity against ALK2-mutant diffuse endogenous pontine glioma (DIPG) cells[2][3] - In vivo, it inhibits the growth of intracranial DIPG tumors and prolongs the survival of nude mice, supporting its potential for treating ALK2-driven tumors[3] - It is widely used as a tool compound for studying the ALK2/BMP signaling pathway. Fibroosting dysplasia of ossifying disease (FOP), lung cancer, and brain tumors [1][2][3] |
| Molecular Formula |
C25H29N3O3
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| Molecular Weight |
419.52
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| Exact Mass |
419.22
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| CAS # |
1627503-67-6
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| Related CAS # |
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| PubChem CID |
91754554
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
567.9±50.0 °C at 760 mmHg
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| Flash Point |
297.3±30.1 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.573
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| LogP |
3.27
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
31
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| Complexity |
522
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
BHUXVRVMMYAXKN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H29N3O3/c1-17-22(19-14-23(29-2)25(31-4)24(15-19)30-3)13-20(16-27-17)18-5-7-21(8-6-18)28-11-9-26-10-12-28/h5-8,13-16,26H,9-12H2,1-4H3
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| Chemical Name |
1-(4-(6-methyl-5-(3,4,5-trimethoxyphenyl)pyridin-3-yl)phenyl)piperazine
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (4.77 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2 mg/mL (4.77 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2 mg/mL (4.77 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3837 mL | 11.9184 mL | 23.8368 mL | |
| 5 mM | 0.4767 mL | 2.3837 mL | 4.7674 mL | |
| 10 mM | 0.2384 mL | 1.1918 mL | 2.3837 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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