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Purity: ≥98%
Gefitinib-based PROTAC 3 is a novel, potent and selective VHL-recruiting PROTAC that induces the degradation of EGFR and EGFR mutants with DC50 of 11.7 nM and 22.3 nM for HCC827 cell (Exon 19 del) and H3255 cell (L858R). Proteolysis targeting chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of endogenous proteins. Herein we describe the development of PROTACs for receptor tyrosine kinases, a protein family yet to be targeted for induced protein degradation. The use of VHL-recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone: direct comparisons of fully functional, target-degrading PROTACs with target-inhibiting variants that contain an inactivated E3 ligase-recruiting ligand show that degradation leads to more potent inhibition of cell proliferation and a more durable and sustained downstream signaling response, and thus addresses the kinome rewiring challenge seen with many receptor tyrosine kinase inhibitors. Combined, these findings demonstrate the ability to target receptor tyrosine kinases for degradation using the PROTAC technology and outline the advantages of this degradation-based approach.
| ln Vitro |
Gefitinib-based PROTAC 3 (25 nM-10 μM; 24 h) was applied to H3255 cells expressing L858R EGFR, and gefitinib-based PROTAC 3 (100 nM-10 μM; 24 h) was applied to exosomes. 19del EGFR in HCC827 cells leads to the retention of WT EGFR while causing the degradation of exon 19 EGFR and mutant isoforms with the L858R activation point mutation [1].
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| Cell Assay |
Western Blot analysis [1]
Cell Types: HCC827 cells expressing exon 19 del EGFR; H3255 cells expressing L858R EGFR Tested Concentrations: 100 nM, 250 nM, 1 μM, 2.5 μM, 10 μM for HCC827 cells; 25 for H3255 cells nM, 100 nM, 1 μM, 2.5 μM, 10 μM Incubation Duration: 24 hrs (hours) Experimental Results: Exon 19 deleted EGFR as well as mutant isoforms containing the L858R activating point mutation were degraded. |
| References |
[1]. Burslem GM, et al. The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study. Cell Chem Biol. 2018 Jan 18;25(1):67-77.e3.
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| Molecular Formula |
C47H57CLFN7O8S
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|---|---|
| Molecular Weight |
934.5140
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| CAS # |
2230821-27-7
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| SMILES |
O=C([C@H]1N(C([C@@H](NC(CCOCCOCCCCCOC2=CC3=C(NC4=CC=C(F)C(Cl)=C4)N=CN=C3C=C2OC)=O)C(C)(C)C)=O)C[C@H](O)C1)NCC5=CC=C(C6=C(C)N=CS6)C=C5
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| InChi Key |
NICKHWYZMNLEPJ-TZSMONEZSA-N
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| InChi Code |
InChI=1S/C47H57ClFN7O8S/c1-29-42(65-28-53-29)31-11-9-30(10-12-31)25-50-45(59)38-22-33(57)26-56(38)46(60)43(47(2,3)4)55-41(58)15-18-63-20-19-62-16-7-6-8-17-64-40-23-34-37(24-39(40)61-5)51-27-52-44(34)54-32-13-14-36(49)35(48)21-32/h9-14,21,23-24,27-28,33,38,43,57H,6-8,15-20,22,25-26H2,1-5H3,(H,50,59)(H,55,58)(H,51,52,54)/t33-,38+,43-/m1/s1
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| Chemical Name |
(2S,4R)-1-((S)-2-(3-(2-((5-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)pentyl)oxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
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| Synonyms |
Gefitinib-based PROTAC-3; Gefitinib-based PROTAC3; Gefitinib-based PROTAC 3
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 : ≥ 60 mg/mL (~64.20 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (2.68 mM) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (2.68 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. View More
Solubility in Formulation 3: ≥ 0.83 mg/mL (0.89 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. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0701 mL | 5.3504 mL | 10.7008 mL | |
| 5 mM | 0.2140 mL | 1.0701 mL | 2.1402 mL | |
| 10 mM | 0.1070 mL | 0.5350 mL | 1.0701 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.
 Small molecule induced degradation of EGFR and mutants.Cell Chem Biol.2018 Jan 18;25(1):67-77.e3. |
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 Selective PROTAC-mediated degradation of HER2 and implications for kinome re-wiring.
PROTAC mediated degradation of c-Met.Cell Chem Biol.2018 Jan 18;25(1):67-77.e3. |
Exon 14-deleted c-Met has increased stability and resistance to HGF-mediated degradation that can be combated by foretinib-based PROTAC 7.
PROTAC mediated internalization. |
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