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Purity: ≥98%
Ad80 is a novel multikinase inhibitor that exhibits potent activity against human RET, BRAF, S6K, and SRC but exhibits much lower activity against mTOR compared to AD57 or AD58. A Ret-kinase-driven Drosophila model of multiple endocrine neoplasia type 2 was used to identify AD57, and kinome-wide drug profiling revealed that AD57 rescues oncogenic Ret-induced lethality while related Ret inhibitors resulted in diminished efficacy and increased toxicity. RET's IC50 value is 4 nM. Human kinase profiles in vitro show that AD80 and AD81 significantly lower mTOR activity than AD57 and AD58 while still inhibiting RET, RAF, SRC, and S6K. In culture, AD80 prevents the growth of MZ-CRC-1 and TT thyroid cancer cells, most likely by inducing apoptosis.
| Targets |
RET V804M (IC50 = 0.4 nM); RET V804L (IC50 = 0.6 nM); Raf; Src; S6 Kinase
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| ln Vitro |
AD80 is a polypharmacological agent that exhibits high efficacy and very low toxicity when used against Ret, Raf, Src, Tor, and S6K. In comparison to AD57 and AD58, AD80 and AD81 significantly reduced mTOR activity and inhibited RET, RAF, SRC, and S6K. For inhibiting the Ras-Erk pathway, AD80 works best. MZ-CRC-1 and TT thyroid cancer cells' ability to proliferate in culture is inhibited by AD80, likely due to the induction of apoptosis. An immunoblot analysis shows that these cells have a significant downregulation of phosphorylated Ret and several downstream biomarkers[1]. Along with AXL, a member of the TAM family of tyrosine kinases, AD80 cooperatively inhibits S6K1. A durable suppression of S6K1-induced signaling and protein synthesis is achieved by AD80's avoidance of S6K1 phosphorylation and mTOR co-association[2].
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| ln Vivo |
In the Drosophila ptc>dRetMEN2B model, oral administration of either AD80 or AD81 significantly improves the efficacy seen with AD57, with a notable 70–90% of animals developing to adulthood. In a mouse xenograft model, AD80 also encourages improved tumor growth inhibition and minimizes body-weight modulation[1]. In mice transplanted with PTEN-deficient leukemia cells, AD80 rescues 50% of the animals[2].
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| Enzyme Assay |
Ad80 is a novel multikinase inhibitor that exhibits potent activity against human RET, BRAF, S6K, and SRC but exhibits much lower activity against mTOR compared to AD57 or AD58. A Ret-kinase-driven Drosophila model of multiple endocrine neoplasia type 2 was used to identify AD57, and kinome-wide drug profiling revealed that AD57 rescues oncogenic Ret-induced lethality while related Ret inhibitors resulted in diminished efficacy and increased toxicity. RET's IC50 value is 4 nM. Human kinase profiles in vitro show that AD80 and AD81 significantly lower mTOR activity than AD57 and AD58 while still inhibiting RET, RAF, SRC, and S6K. In culture, AD80 prevents the growth of MZ-CRC-1 and TT thyroid cancer cells, most likely by inducing apoptosis.
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| Cell Assay |
MZ-CRC-1 (MEN2B) and TT (MEN2A)cell viability is measured using the MTT assay after cells have been exposed to AD80 (0.2 nM to 20 μM) for 7 days[1].
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| Animal Protocol |
Mice: Mice with established, expanding tumors are divided into groups that receive either a vehicle or a drug treatment. For each experiment (vehicle vs. AD57; vehicle vs. AD80; vehicle vs. Vandetanib), a similar range of tumor sizes is chosen. One time per day, five times per week, oral gavage (PO; per os or by mouth) is used to administer the vehicle, AD57 (20 mg/kg), AD80 (30 mg/kg), or Vandetanib (50 mg/kg). Three times a week, measurements of the body weight and tumor are taken[2].
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| References |
| Molecular Formula |
C22H19F4N7O
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| Molecular Weight |
473.43
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| Exact Mass |
473.16
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| Elemental Analysis |
C, 55.81; H, 4.05; F, 16.05; N, 20.71; O, 3.38
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| CAS # |
1384071-99-1
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| Related CAS # |
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| Appearance |
Solid powder
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| SMILES |
CC(C)N1C2=NC=NC(=C2C(=N1)C3=CC=C(C=C3)NC(=O)NC4=C(C=CC(=C4)C(F)(F)F)F)N
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| InChi Key |
CYORWDWRQMVGHN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H19F4N7O/c1-11(2)33-20-17(19(27)28-10-29-20)18(32-33)12-3-6-14(7-4-12)30-21(34)31-16-9-13(22(24,25)26)5-8-15(16)23/h3-11H,1-2H3,(H2,27,28,29)(H2,30,31,34)
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| Chemical Name |
1-[4-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea
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| Synonyms |
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| HS Tariff Code |
2934.99.03.00
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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) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1122 mL | 10.5612 mL | 21.1224 mL | |
| 5 mM | 0.4224 mL | 2.1122 mL | 4.2245 mL | |
| 10 mM | 0.2112 mL | 1.0561 mL | 2.1122 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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Balanced kinase polypharmacology provides optimal efficacy and toxicityNature.2012 Jun 6;486(7401):80-4. |
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