| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
IC50: 2 nM (human smo), 4 nM (mouse smo)[1]
LEQ506 targets Smoothened (Smo), a seven-transmembrane G protein-coupled receptor that serves as the key transducer of the Hedgehog (Hh) signaling pathway. In the absence of Hh ligand, Smo is inhibited by the Patched receptor. When Hh ligand binds to Patched, Smo is activated, leading to downstream signaling through the Gli family of transcription factors. Smo is a validated therapeutic target in Hh-driven cancers, including basal cell carcinoma and medulloblastoma. LEQ506 binds to Smo with high affinity (IC₅₀ = 2 nM for human Smo), blocking its activation and downstream Hh signaling. The compound is a second-generation Smo inhibitor, developed to overcome resistance to first-generation inhibitors. |
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| ln Vitro |
LEQ506, a smoothened (Smo) inhibitor of the second generation, with IC50 values of 2 nM in humans and 4 nM in mice. The quantity of Gli mRNA in a human cell line (HEPM) indicates that LEQ506 inhibits Hedgehog (Hh) signaling, with an IC50 that is approximately 6-fold lower than that of Compound 2[1]. LEQ506 consistently reduces Gli1 mRNA by approximately 70–80%, making it an effective chemical. LEQ506 (at 1%), an effective drug with an inhibition of 80 to 90% for Gli1 and 60 to 70% for Ptch1, also has a tendency to preferentially inhibit Gli1 mRNA rather than Ptch1 mRNA[2].
In vitro studies have demonstrated that LEQ506 is a potent inhibitor of Smo with IC₅₀ values of 2 nM and 4 nM for human and mouse Smo, respectively. The compound inhibits Hh signaling in various cell-based assays, blocking Gli-dependent transcription and downstream target gene expression. LEQ506 shows activity against Smo mutants that confer resistance to first-generation Smo inhibitors such as vismodegib and sonidegib. In cancer cell lines driven by Hh signaling, LEQ506 treatment results in reduced cell proliferation and induction of apoptosis. The compound's potency and selectivity make it a valuable tool for studying Hh signaling and developing therapies for Hh-driven cancers. |
| ln Vivo |
In vivo studies have demonstrated that LEQ506 exhibits anti-tumor activity in preclinical models of Hh-driven cancers. In mouse xenograft models of medulloblastoma and basal cell carcinoma, oral administration of LEQ506 leads to significant tumor growth inhibition. The compound's efficacy is associated with reduced Hh signaling in tumor tissues, as measured by decreased expression of Gli target genes. LEQ506 has been evaluated in multiple preclinical models to assess its therapeutic potential. The compound's favorable pharmacokinetic properties support once-daily oral dosing. Clinical trials have been conducted in patients with advanced solid tumors, medulloblastoma, and basal cell carcinoma.
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| Enzyme Assay |
Cell-free biochemical assays for LEQ506 typically measure binding to Smo or inhibition of Smo-mediated signaling. A standard protocol involves radioligand binding assays using [³H]-cyclopamine or other Smo ligands. Membranes from Smo-expressing cells are incubated with varying concentrations of LEQ506 (0.1-100 nM) and the radioligand, and bound radioactivity is measured by scintillation counting. Alternatively, cell-free assays using Smo activation of downstream components can be used. IC₅₀ values are determined from competition binding curves using nonlinear regression analysis. Assays are performed in triplicate with appropriate positive and negative controls.
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| Cell Assay |
Cellular assays for LEQ506 typically use Hh-responsive cell lines (e.g., Shh-Light2 cells or primary fibroblasts) to assess inhibition of Hh signaling. A standard protocol involves culturing cells in 96-well plates, treating with LEQ506 at concentrations ranging from 0.1-100 nM for 24-48 hours, and stimulating with Shh ligand or Smo agonists. Hh signaling activity is assessed using Gli-luciferase reporter assays or by measuring expression of Gli target genes (e.g., Gli1, PTCH1) by qPCR. Cell proliferation is assessed by MTT or CellTiter-Glo assays. The compound's effects on Smo localization and signaling can be assessed by immunofluorescence microscopy.
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| Animal Protocol |
In vivo studies for LEQ506 are typically conducted in mouse xenograft models of Hh-driven cancers. A standard protocol involves subcutaneous or orthotopic implantation of medulloblastoma or basal cell carcinoma cells in immunocompromised mice. When tumors reach a volume of approximately 100-200 mm³, mice are randomized and treated with LEQ506 administered orally at doses of 1-30 mg/kg, typically once daily for 2-4 weeks. Tumor volume is measured with calipers twice weekly, and body weight is monitored for toxicity. At study termination, tumors are excised for analysis of Hh signaling biomarkers by qPCR or immunohistochemistry. Pharmacodynamic effects are assessed in tumor tissues.
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| ADME/Pharmacokinetics |
Pharmacokinetic studies of LEQ506 have demonstrated that the compound exhibits favorable PK properties supporting oral administration. Following oral administration, LEQ506 shows good absorption and systemic exposure, supporting once-daily dosing. The compound's half-life is sufficient for sustained Smo inhibition. LEQ506 distributes to target tissues, enabling effective inhibition of Hh signaling in tumors. The compound's favorable PK profile has been characterized in preclinical species and in clinical studies. Detailed PK parameters including Cmax, Tmax, AUC, and half-life have been determined.
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| Toxicity/Toxicokinetics |
Toxicological studies of LEQ506 have been conducted as part of preclinical and clinical development. The compound's safety profile has been evaluated in rodent and non-rodent species, as well as in clinical trials. At therapeutic doses, LEQ506 is generally well-tolerated with an acceptable safety margin. Observed toxicities are consistent with on-target Smo inhibition and include effects on tissues where Hh signaling is important for development and homeostasis. Common adverse effects may include muscle spasms, dysgeusia, and alopecia, similar to other Smo inhibitors. Comprehensive toxicology assessments have been conducted to support clinical development.
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| References |
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| Additional Infomation |
LEQ506 has been used in clinical trials for the treatment of advanced solid tumors, relapsed or refractory medulloblastoma, and locally advanced or metastatic basal cell carcinoma. The smoothed antagonist LEQ506 is a small molecule smoothed (Smo) antagonist with high oral bioavailability and potential antitumor activity. LEQ506 selectively binds to the Hedgehog (Hh) ligand cell surface receptor Smo, thereby inhibiting the Hh signaling pathway and subsequently suppressing tumor cell growth. The Hh signaling pathway plays a crucial role in cell growth, differentiation, and repair. Dysregulation of Hh pathway signaling activation and uncontrolled cell proliferation observed in various cancers may be related to mutations in the Hh ligand cell surface receptor Smo.
LEQ506 (NVP-LEQ506) is an investigational compound that has been evaluated in clinical trials for the treatment of advanced solid tumors, relapsed or refractory medulloblastoma, and locally advanced or metastatic basal cell carcinoma. The compound was developed by Novartis. As a second-generation Smo inhibitor, LEQ506 was designed to overcome resistance to first-generation Smo inhibitors such as vismodegib and sonidegib. Clinical trials have assessed its safety, tolerability, pharmacokinetics, and preliminary efficacy. As of the available information, LEQ506 has not received regulatory approval for clinical use. The compound remains a valuable research tool for studying Hh signaling and as a potential therapeutic option for Hh-driven cancers. |
| Molecular Formula |
C25H32N6O
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|---|---|
| Molecular Weight |
432.56
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| Exact Mass |
432.264
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| CAS # |
1204975-42-7
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| PubChem CID |
45100669
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| Appearance |
White to yellow solid powder
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| LogP |
3.546
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
32
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| Complexity |
597
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@@H]1CN(CCN1C2=NC=C(N=C2)C(C)(C)O)C3=NN=C(C(=C3C)C)CC4=CC=CC=C4
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| InChi Key |
POERAARDVFVDLO-QGZVFWFLSA-N
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| InChi Code |
InChI=1S/C25H32N6O/c1-17-16-30(11-12-31(17)23-15-26-22(14-27-23)25(4,5)32)24-19(3)18(2)21(28-29-24)13-20-9-7-6-8-10-20/h6-10,14-15,17,32H,11-13,16H2,1-5H3/t17-/m1/s1
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| Chemical Name |
2-[5-[(2R)-4-(6-benzyl-4,5-dimethylpyridazin-3-yl)-2-methylpiperazin-1-yl]pyrazin-2-yl]propan-2-ol
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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 |
| 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) |
DMSO: ≥ 100 mg/mL (231.18 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3118 mL | 11.5591 mL | 23.1182 mL | |
| 5 mM | 0.4624 mL | 2.3118 mL | 4.6236 mL | |
| 10 mM | 0.2312 mL | 1.1559 mL | 2.3118 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.
Link: https://clinicaltrials.gov/ct2/show/NCT01106508
Conditions:Advanced Solid Tumors|Recurrent or Refractory Medulloblastoma|Locally Advanced or Metastatic Basal Cell CarcinomaProducts are for research use only; We do not sell to patients
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