| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg | |||
| Other Sizes |
| Targets |
K-975 targets TEAD, a transcription factor that is a key component of the Hippo signaling pathway. TEAD forms a complex with the transcriptional coactivators YAP (yes-associated protein) or TAZ (transcriptional coactivator with PDZ-binding motif), and this complex drives the expression of genes involved in cell proliferation, survival, and migration. Overactivation of YAP/TAZ-TEAD signaling is associated with oncogenesis in various cancers. K-975 binds to the palmitate-binding pocket of TEAD, preventing its association with YAP/TAZ. By inhibiting this protein-protein interaction, K-975 blocks the transcriptional activity of the YAP/TAZ-TEAD complex and suppresses oncogenic gene expression.
|
|---|---|
| ln Vitro |
Cell proliferation in malignant pleural mesothelioma (MPM) cell lines lacking NF2 is inhibited by K-975 (0.1–10,000 nM; 144 h) [1]. In NCI-H226 cells, the protein-protein interaction (PPI) between Halo-YAP and endogenous TEAD1/4 as well as Halo-TAZ and TEAD1/4 is inhibited by K-975 (10–10,000 nM; 24 hours) [1]. K-975 (0.1-10000 nM; 24 h) does not reduce reporter gene activity in NCI-H661/NRF2-Luc cells, but it significantly suppresses reporter gene activity in NCI-H661/CTGF-Luc cells, with a maximum inhibition of around 70%. [1]. In NCI-H226 cells, K-975 (1–10,000 nM; 24 hours) decreases the expression of NPPB, CTGF, and IGFBP3 mRNA and enhances the expression of FBXO32 mRNA [1].
In vitro, K-975 inhibits the proliferation of malignant pleural mesothelioma (MPM) cell lines that do not express NRF2. The compound inhibits protein-protein interactions between Halo-TAZ and TEAD1/4 and between Halo-YAP and endogenous TEAD1/4 in NCI-H226 cells. K-975 inhibits reporter gene activity in NCI-H661/CTGF-Luc cells with a maximum inhibition of approximately 70%. The compound's ability to disrupt YAP/TAZ-TEAD interactions makes it a valuable tool for studying the Hippo signaling pathway and its role in cancer. |
| ln Vivo |
K-975 (10-300 mg/kg; given orally twice daily for 14 days) reduces tumor growth by decreasing YAP1/TAZ-TEAD signaling in an MPM xenograft mice model [1].
In vivo, K-975 has shown potent antitumor effects in malignant pleural mesothelioma. The compound is orally active and has been evaluated in preclinical models of YAP/TAZ-driven cancers. K-975's ability to inhibit TEAD and disrupt YAP/TAZ-TEAD interactions makes it a promising candidate for the treatment of cancers with dysregulated Hippo signaling. |
| Enzyme Assay |
K-975's inhibition of TEAD is assessed using biochemical and cell-based assays. In biochemical assays, the binding of K-975 to TEAD is assessed using surface plasmon resonance (SPR) or fluorescence polarization. In cell-based assays, the inhibition of YAP/TAZ-TEAD protein-protein interactions is assessed using co-immunoprecipitation or proximity ligation assays; TEAD transcriptional activity is assessed using luciferase reporter gene assays; cell proliferation is assessed by MTT or CellTiter-Glo assays. These assays provide quantitative information on the potency and mechanism of action of K-975.
|
| Cell Assay |
Cell proliferation experiment [1]
Cell Types: MPM that does not express NF2 and malignant MPM that expresses NF2 Cell Tested Concentrations: 0.1, 1, 10, 100, 1000, 10000 nM Incubation Duration: 144 hrs (hours) Experimental Results: Strong inhibitory effect on NF2-non Expressing cell lines are higher than those expressing NF2. Inhibits the proliferation of MSTO-211H cells, an NF2-expressing cell line. Western Blot Analysis[1] Cell Types: NCI-H226 Cell Tested Concentrations: 10, 100, 1000, 10000 nM Incubation Duration: 24 hrs (hours) Experimental Results: TEAD1-YAP1 PPI and TEAD4-YAP1 PPI were inhibited. Inhibits TEAD1-TAZ PPI and TEAD4-TAZ PPI. K-975 is tested on cultured cancer cells, including malignant pleural mesothelioma cell lines (e.g., NCI-H226, NCI-H661) and other YAP/TAZ-driven cancer cell lines. Cells are treated with varying concentrations of K-975; YAP/TAZ-TEAD protein-protein interactions are assessed by co-immunoprecipitation or proximity ligation assays; TEAD transcriptional activity is assessed by reporter gene assays or qPCR for TEAD target genes (e.g., CTGF, CYR61); cell proliferation is assessed by MTT or CellTiter-Glo assays; apoptosis is assessed by Annexin V staining. These cell-based assays demonstrate the mechanism of action and antiproliferative activity of K-975. |
| Animal Protocol |
Animal/Disease Models: Male SCID (severe combined immunodeficient) mouse (5 weeks) injected with NCI-H226 or MSTO-211H cells [1]
Doses: 10, 30, 100, 300 mg/kg Route of Administration: Orally twice (two times) daily for 14 days Experimental Results: Performance Tumor effects in potent anti-MPM sc xenograft mouse models. diminished expression of CTGF, IGFBP3, and NPPB, and increased expression of FBXO32 in the NCI-H226 xenograft model. K-975 has been evaluated in animal models of malignant pleural mesothelioma and other YAP/TAZ-driven cancers. In these models, K-975 is administered orally at various doses; tumor growth inhibition is assessed by measuring tumor volume; YAP/TAZ-TEAD signaling is assessed by measuring the expression of TEAD target genes in tumor tissue. These in vivo studies provide evidence for the efficacy of K-975. |
| ADME/Pharmacokinetics |
Pharmacokinetic studies indicate that K-975 is orally active. The compound's absorption, distribution, metabolism, and excretion have been characterized in preclinical studies. K-975 achieves therapeutic concentrations in plasma and tissues following oral administration. The compound's pharmacokinetic properties support once-daily oral dosing.
|
| Toxicity/Toxicokinetics |
Toxicological data for K-975 is limited in the available literature. As a TEAD inhibitor, K-975 may have effects on normal cells as well as cancer cells, given the role of the Hippo pathway in tissue homeostasis. Comprehensive toxicological studies are needed to evaluate the safety profile of K-975.
|
| References | |
| Additional Infomation |
K-975 is a potent, selective, and orally active TEAD inhibitor that strongly inhibits protein-protein interactions between YAP1/TAZ and TEAD. The compound binds to the palmitate-binding pocket of TEAD, preventing its association with YAP/TAZ. K-975 inhibits the proliferation of malignant pleural mesothelioma cell lines and has shown potent antitumor effects in preclinical models. The compound represents a promising therapeutic approach for YAP/TAZ-driven cancers, including malignant pleural mesothelioma. K-975 is not approved as a therapeutic agent and is used for research purposes only.
|
| Molecular Formula |
C16H14CLNO2
|
|---|---|
| Molecular Weight |
287.7409
|
| Exact Mass |
287.071
|
| CAS # |
2563855-03-6
|
| PubChem CID |
155353714
|
| Appearance |
White to off-white solid powder
|
| LogP |
4.2
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
2
|
| Rotatable Bond Count |
4
|
| Heavy Atom Count |
20
|
| Complexity |
339
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
ClC1C([H])=C([H])C(=C([H])C=1[H])OC1C([H])=C(C([H])=C([H])C=1C([H])([H])[H])N([H])C(C([H])=C([H])[H])=O
|
| InChi Key |
KPXAHQSIROUBPH-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C16H14ClNO2/c1-3-16(19)18-13-7-4-11(2)15(10-13)20-14-8-5-12(17)6-9-14/h3-10H,1H2,2H3,(H,18,19)
|
| Chemical Name |
N-[3-(4-chlorophenoxy)-4-methylphenyl]prop-2-enamide
|
| 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 |
| 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 : ~220 mg/mL (~764.58 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 5.5 mg/mL (19.11 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 55.0 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: ≥ 5.5 mg/mL (19.11 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 55.0 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: ≥ 5.5 mg/mL (19.11 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 | 3.4754 mL | 17.3768 mL | 34.7536 mL | |
| 5 mM | 0.6951 mL | 3.4754 mL | 6.9507 mL | |
| 10 mM | 0.3475 mL | 1.7377 mL | 3.4754 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
