| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| 50mg |
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| Other Sizes |
| Targets |
RAS/MAPK signaling pathway components, specifically BRAF and Lk6/MKNK (a kinase related to MAPK signal integration). APS6-45 is a TCI that modulates the activity of these targets, leading to broad inhibition of the RAS pathway.
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| ln Vitro |
In a soft agar experiment, APS6-45 (3-30 nM; 3 weeks) significantly inhibits the growth of TT human Medullary Thyroid Carcinoma (MTC) cell colonies[1]. RAS pathway activity signaling in human MTC cell lines TT and MZ-CRC-1 is substantially inhibited by APS6-45 (1 μM; 1 h)[1].
In soft agar assays, APS6-45 (3-30 nM for 3 weeks) significantly inhibits colony growth of TT human medullary thyroid carcinoma (MTC) cells. At 1 uM for 1 hour, it strongly inhibits RAS pathway activity signaling in human MTC cell lines TT and MZ-CRC-1. |
| ln Vivo |
APS6-45 (10 mg/kg; po daily for 30 d) does not alter body weight but instead prevents the formation of TT tumors in mice[1]. In mice, APS6-45 (0.1-160 mg/kg; one po) had no discernible harmful effects[1]. In mice, APS6-45 (20 mg/kg; one dose) had a lengthy half-life (5.6 h), a Cmax of 9.7 µM, and an AUC0-24 of 123.7 µM·h[1].
In mice, oral administration of APS6-45 (10 mg/kg daily for 30 days) prevents the formation of TT tumors and significantly inhibits the growth of established tumors without affecting body weight. These effects demonstrate its in vivo antitumor efficacy and tolerability. |
| Enzyme Assay |
Not reported. As a TCI that targets protein kinases, a cell-free assay could be performed using purified BRAF or Lk6/MKNK enzymes. The kinase is incubated with a substrate peptide, ATP, and varying concentrations of APS6-45. The amount of phosphorylated substrate is measured using a luminescence-based or fluorescence-based method to determine IC50 values, though specific values for these targets are not reported.
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| Cell Assay |
TT human medullary thyroid carcinoma (MTC) cells are seeded in 6-well plates and treated with APS6-45 (3-30 nM) for 3 weeks. Colonies are fixed, stained with crystal violet, and counted to assess anchorage-independent growth. For signaling studies, cells are treated with 1 uM APS6-45 for 1 hour, lysed, and analyzed by Western blot for phospho-ERK and total ERK.
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| Animal Protocol |
Animal/Disease Models: Female nude mice (6 weeks) are implanted with TT cells[1]
Doses: 10 mg/kg Route of Administration: Po daily for 30 days Experimental Results: Led to partial or complete responses in 75% and was well tolerated. Animal/Disease Models: Male ICR mice (6 weeks of age)[1] Doses: 20 mg/kg (pharmacokinetic/PK Analysis) Route of Administration: A single po Experimental Results: T1/2=5.6 h, Cmax=9.7 µM, AUC0-24=123.7 µM •h. In vivo efficacy is evaluated in a mouse xenograft model using TT human MTC cells. Nude mice are implanted subcutaneously with TT cells. When tumors reach a certain size, APS6-45 is administered orally daily at 10 mg/kg for 30 days. Tumor volume is measured twice weekly with calipers. At study termination, tumors are excised and analyzed for RAS/MAPK pathway inhibition by Western blot. Body weight is monitored as a toxicity indicator. |
| ADME/Pharmacokinetics |
APS6-45 is orally bioavailable. Oral dosing at 20 mg/kg reaches a plasma concentration of approximately 10 uM. It has a relatively long half-life (5.6 hours), and its overall pharmacokinetic parameters are similar to sorafenib, an approved multi-kinase inhibitor. This profile supports once-daily oral dosing for in vivo studies.
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| Toxicity/Toxicokinetics |
In mice, APS6-45 at doses up to 160 mg/kg (single oral dose) and 10 mg/kg daily for 30 days caused no detectable toxic effects or changes in body weight. This suggests a favorable safety margin for this research compound at efficacious doses, with a clear separation between therapeutically active and toxic doses.
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| References | |
| Additional Infomation |
APS6-45 represents a new class of inhibitors known as tumor-calibrated inhibitors (TCIs), which are designed to have reduced activity towards normal tissues while maintaining efficacy in cancer cells. Its unique mechanism of inhibiting multiple nodes in the RAS/MAPK pathway (BRAF and Lk6/MKNK) may allow it to overcome resistance seen with selective BRAF inhibitors in cancers like melanoma. It has also been shown to strongly inhibit Ret-mediated transformation, suggesting broader applications in RET-driven cancers, such as medullary thyroid carcinoma.
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| Molecular Formula |
C23H16F8N4O3
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|---|---|
| Molecular Weight |
548.38537311554
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| Exact Mass |
548.109
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| CAS # |
2188236-41-9
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| PubChem CID |
131953288
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
4.9
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
38
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| Complexity |
806
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC(C(F)(F)F)(C(F)(F)F)C1C=CC(=C(C=1)NC(NC1C=CC(=CC=1)OC1C=CN=C(C(NC)=O)C=1)=O)F
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| InChi Key |
MVUPJRHPAMCBQJ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H16F8N4O3/c1-32-19(36)18-11-15(8-9-33-18)38-14-5-3-13(4-6-14)34-20(37)35-17-10-12(2-7-16(17)24)21(25,22(26,27)28)23(29,30)31/h2-11H,1H3,(H,32,36)(H2,34,35,37)
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| Chemical Name |
4-[4-[[2-fluoro-5-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide
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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: 250 mg/mL (455.88 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.79 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 20.8 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 | 1.8235 mL | 9.1176 mL | 18.2352 mL | |
| 5 mM | 0.3647 mL | 1.8235 mL | 3.6470 mL | |
| 10 mM | 0.1824 mL | 0.9118 mL | 1.8235 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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