| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 100mg | |||
| Other Sizes |
| Targets |
The primary target of deltasonamide is PDE6δ, a prenyl-binding protein that plays a critical role in the trafficking of farnesylated proteins, including KRas. PDE6δ binds to the farnesyl moiety of KRas and facilitates its transport to cellular membranes, where KRas exerts its signaling functions. By binding to PDE6δ with picomolar affinity (Kd = 203 pM), deltasonamide disrupts the PDE6δ–KRas interaction, preventing KRas from reaching the membrane. This leads to the mislocalization of KRas to the cytoplasm and impairment of KRas-mediated signaling pathways, including the MAPK and PI3K pathways. The compound's high selectivity for PDE6δ over other proteins minimizes off-target effects. Targeting the PDE6δ–KRas interaction represents a novel approach to inhibiting KRas, which has traditionally been considered "undruggable."
|
|---|---|
| ln Vitro |
Deltasonamide 1 can block PDE6δ-KRas at a concentration of 203 pM[1]. With a picomolar affinity, deltasonamide 1 binds to PDE6δ via up to seven hydrogen bonds [1]. Swelling is significantly reduced by deltasonamide 1[1].
In vitro, deltasonamide demonstrates potent inhibition of the PDE6δ–KRas interaction with a Kd of 203 pM. It binds to PDE6δ via up to seven hydrogen bonds, contributing to its high affinity and selectivity. The compound inhibits PDE6δ–KRas interaction in cells with a Kd of 85 nM. By disrupting the PDE6δ–KRas interaction, deltasonamide prevents KRas membrane localization and impairs KRas-mediated signaling. This leads to reduced proliferation and survival of KRas-dependent cancer cells. The compound's picomolar affinity for PDE6δ makes it one of the most potent inhibitors of this protein-protein interaction reported to date. Its in vitro activity has been characterized using biochemical binding assays and cell-based functional assays. |
| ln Vivo |
In vivo, deltasonamide has demonstrated efficacy in preclinical tumor models. The compound significantly reduces tumor swelling in animal models, indicating its potential as an anticancer agent. By disrupting the PDE6δ–KRas interaction, deltasonamide impairs KRas membrane localization and signaling, leading to reduced tumor growth. The compound can be used for the research of tumors. Its in vivo activity supports the therapeutic potential of targeting the PDE6δ–KRas interaction for KRas-driven cancers. However, comprehensive in vivo efficacy studies in various tumor models, including xenografts and genetically engineered mouse models, would be necessary to fully characterize the compound's antitumor activity and establish optimal dosing regimens.
|
| Enzyme Assay |
In vitro binding assays for deltasonamide measure its affinity for PDE6δ. Surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) techniques are commonly used to determine the Kd value for the PDE6δ–deltasonamide interaction. In these assays, purified PDE6δ protein is immobilized, and varying concentrations of deltasonamide are flowed over the surface to measure binding kinetics and affinity. The compound binds to PDE6δ via up to seven hydrogen bonds, contributing to its picomolar affinity. Competition binding assays can also be performed using fluorescently labeled PDE6δ ligands to confirm the compound's binding and determine its potency. These biochemical assays are essential for characterizing the compound's mechanism of action.
|
| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: RTCA of hPDAC cell line. Tested Concentrations: 0.375, 0.75, 1.5, 3, 6, 12 μM. Incubation Duration: 60 hrs (hours). Experimental Results: Inhibition of proliferation of human pancreatic cancer cell lines. In vitro cell-based assays for deltasonamide evaluate its ability to disrupt the PDE6δ–KRas interaction in living cells and impair KRas signaling. Cells expressing KRas are treated with varying concentrations of deltasonamide, and the localization of KRas is assessed by immunofluorescence microscopy or cell fractionation followed by Western blot. The disruption of the PDE6δ–KRas interaction leads to the mislocalization of KRas from the membrane to the cytoplasm. KRas-mediated signaling can be assessed by measuring the phosphorylation of downstream effectors such as ERK and AKT using phospho-specific antibodies. Cell proliferation and survival are evaluated using standard assays such as MTT or Colony Formation assays. These assays confirm the compound's mechanism of action and provide functional data on its cellular activity. |
| Animal Protocol |
In vivo animal studies for deltasonamide have been conducted in tumor models to evaluate its anticancer efficacy. In a typical study, immunocompromised mice are implanted with KRas-driven tumor cells to form subcutaneous xenografts. Once tumors reach a certain size, mice are randomized into treatment groups receiving deltasonamide or vehicle control. Tumor volume and body weight are monitored regularly. At study endpoint, tumors are harvested for analysis of KRas localization, signaling pathway activation, and apoptosis markers. The compound significantly reduces tumor swelling in these models. These studies are crucial for validating the therapeutic potential of PDE6δ–KRas inhibition and for guiding dose selection for future development.
|
| ADME/Pharmacokinetics |
Deltasonamide has a molecular weight of 647.25 and a chemical formula of C₃₀H₃₉ClN₆O₄S₂. As a small-molecule inhibitor with picomolar affinity for PDE6δ, the compound is expected to have favorable drug-like properties. Detailed pharmacokinetic parameters such as absorption, distribution, metabolism, and excretion are not extensively reported in the publicly available literature. The compound is typically formulated for systemic administration in animal studies. Its high affinity and selectivity for PDE6δ suggest that it may have a favorable pharmacokinetic profile with good bioavailability and tissue distribution. However, comprehensive PK studies would be necessary to fully characterize the compound's ADME properties.
|
| Toxicity/Toxicokinetics |
Specific toxicity data for deltasonamide is not extensively reported in the publicly available literature. As a highly selective inhibitor of the PDE6δ–KRas interaction, the compound's safety profile would depend on the role of PDE6δ in normal cellular function. PDE6δ is involved in the trafficking of multiple farnesylated proteins, not just KRas, and its inhibition could affect the function of other proteins that depend on PDE6δ for membrane localization. However, the compound's high selectivity for PDE6δ over other proteins may minimize off-target toxicity. Comprehensive toxicology studies, including assessments of genotoxicity, acute and chronic toxicity, and effects on major organ systems, would be required before clinical development. The compound is currently classified as a research-grade chemical and is not intended for human use.
|
| References | |
| Additional Infomation |
Deltasonamide (Deltasonamide 1) is a third-generation, highly selective small-molecule inhibitor of the PDE6δ–KRas protein–protein interaction. It binds to PDE6δ with picomolar affinity (Kd = 203 pM) via up to seven hydrogen bonds. By disrupting the PDE6δ–KRas interaction, the compound prevents KRas membrane localization and impairs KRas-mediated signaling. Deltasonamide significantly reduces tumor swelling in preclinical models. It has a molecular weight of 647.25. The compound represents a novel approach to targeting KRas-driven cancers and has not received FDA approval for any indication.
|
| Molecular Formula |
C30H39CLN6O4S2
|
|---|---|
| Molecular Weight |
647.25146317482
|
| Exact Mass |
646.216
|
| CAS # |
2088485-33-8
|
| Related CAS # |
Deltasonamide 2 (TFA);2235358-74-2;Deltasonamide 2 hydrochloride;2448341-55-5;Deltasonamide 1 TFA;2235358-73-1;Deltasonamide 2;2088485-34-9
|
| PubChem CID |
124080849
|
| Appearance |
White to off-white solid powder
|
| LogP |
4.1
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
10
|
| Rotatable Bond Count |
12
|
| Heavy Atom Count |
43
|
| Complexity |
1060
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
ClC1C=CC(=CC=1)CN(C1CCCC1)S(C1C=CC(=CC=1)S(N(CC1C=CN=C(NC)N=1)CC1CCNCC1)(=O)=O)(=O)=O
|
| InChi Key |
FWBBCSKXUXMTJY-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C30H39ClN6O4S2/c1-32-30-34-19-16-26(35-30)22-36(20-24-14-17-33-18-15-24)42(38,39)28-10-12-29(13-11-28)43(40,41)37(27-4-2-3-5-27)21-23-6-8-25(31)9-7-23/h6-13,16,19,24,27,33H,2-5,14-15,17-18,20-22H2,1H3,(H,32,34,35)
|
| Chemical Name |
4-N-[(4-chlorophenyl)methyl]-4-N-cyclopentyl-1-N-[[2-(methylamino)pyrimidin-4-yl]methyl]-1-N-(piperidin-4-ylmethyl)benzene-1,4-disulfonamide
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~66.67 mg/mL (~103.01 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.86 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 25.0 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: ≥ 2.5 mg/mL (3.86 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5450 mL | 7.7250 mL | 15.4500 mL | |
| 5 mM | 0.3090 mL | 1.5450 mL | 3.0900 mL | |
| 10 mM | 0.1545 mL | 0.7725 mL | 1.5450 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/NCT07042100
Conditions:Advanced Solid TumorsProducts are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
