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Mavelertinib (formerly PF-06747775; PF06747775) is a mutant-selective, orally bioactive and irreversible/covalent inhibitor of the epidermal growth factor receptor (EGFR) T790M. It has potential antineoplastic activity. As as EGFR T790M inhibitor, PF-06747775 specifically binds to and inhibits EGFR T790M, a secondarily acquired resistance mutation, which prevents EGFR-mediated signaling and leads to cell death in EGFR T790M-expressing tumor cells. Compared to some other EGFR inhibitors, PF-06747775 may have therapeutic benefits in tumors with T790M-mediated drug resistance.
| ln Vitro |
Selectivity against wild-type EGFR is demonstrated by mavelertinib (IC50=307 nM)[1]. Less than 50% of non-kinase targets are affected or inhibited by mavelertinib (10 μM) [1]. With an IC50 > 100 μM, mavelertinib suppresses hERG26 current[1].
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| ln Vivo |
Following oral dosing (1 in mice, 30 in rats, and 3 mg/kg in dogs), mavelertinib has low to moderate oral bioavailability (60% in mice, 11% in rats, and 66% in dogs) [1]. Intravenous injection (1 mg/kg) in small rats, rats, and dogs [1].
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| Animal Protocol |
Animal/Disease Models: Female Nu/nu (nude) mice [1]
Doses: 1 mg/kg (pharmacokinetic/PK/PK analysis) Route of Administration: Po and iv Administration Experimental Results: Oral bioavailability (60%), T1/2 (1.48 h). |
| References |
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| Additional Infomation |
Mavelertinib is under investigation in clinical trial NCT02349633 (Study for Patients With NSCLC EGFR Mutations (Del 19 or L858R +/- T790M)).
Mavelertinib is an orally available inhibitor of the epidermal growth factor receptor (EGFR) mutant form T790M, with potential antineoplastic activity. Mavelertinib specifically binds to and inhibits EGFR T790M, a secondary acquired resistance mutation, which prevents EGFR-mediated signaling and leads to cell death in EGFR/T790M-expressing tumor cells. Compared to some other EGFR inhibitors, PF-06747775 may have therapeutic benefits in tumors with T790M-mediated drug resistance. This agent shows minimal activity against wild-type EGFR (WT EGFR), and does not cause dose-limiting toxicities that occur during the use of non-selective EGFR inhibitors, which can inhibit WT EGFR. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. |
| Molecular Formula |
C18H22FN9O2
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|---|---|
| Molecular Weight |
415.424785137177
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| Exact Mass |
415.188
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| CAS # |
1776112-90-3
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| PubChem CID |
91668194
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Index of Refraction |
1.715
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| LogP |
-1.82
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
643
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CN1C=C(C(=N1)OC)NC2=C3C(=NC(=N2)N4C[C@H]([C@@H](C4)F)NC(=O)C=C)N(C=N3)C
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| InChi Key |
JYIUNVOCEFIUIU-GHMZBOCLSA-N
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| InChi Code |
InChI=1S/C18H22FN9O2/c1-5-13(29)21-11-8-28(6-10(11)19)18-23-15(14-16(24-18)26(2)9-20-14)22-12-7-27(3)25-17(12)30-4/h5,7,9-11H,1,6,8H2,2-4H3,(H,21,29)(H,22,23,24)/t10-,11-/m1/s1
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| Chemical Name |
N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide
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| Synonyms |
PF-06747775 PF6747775PF06747775 PF 6747775PF 06747775 PF-6747775
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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 : ~47.5 mg/mL (~114.34 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 | 2.4072 mL | 12.0360 mL | 24.0720 mL | |
| 5 mM | 0.4814 mL | 2.4072 mL | 4.8144 mL | |
| 10 mM | 0.2407 mL | 1.2036 mL | 2.4072 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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