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Purity: ≥98%
Zipalertinib (TAS6417; CLN-081; TAS-6417) is a novel, potent, orally bioavailable and selective covalent/irreversible EGFR inhibitor with anticancer activity. It acts by binding covalently to cysteine residue at 797 in the ATP-binding site of the EGFR hinge region. TAS6417 is an efficacious drug candidate for patients with NSCLC, with IC50 values ranging from 1.1-8.0 nM. TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model.
| ln Vitro |
In NSCLC cell lines containing EGFR exon 20 insertions, zipalertinib (TAS6417) suppresses EGFR phosphorylation and downstream molecules, resulting in caspase activation [1]. Targeting the most prevalent EGFR (exon 19 deletion and L858R), zipalertinib (TAS6417) works best against cells with the EGFR-T790M (1/2 generation TKI mutations) mutation [2]. Recombinant EGFR cysteine residue 797 is covalently modified by zipalertinib (TAS6417). Cell growth is inhibited by zipalertinib (TAS6417), which blocks the transmission of the EGFR signal. In intermittently driven NSCLC cells, EGFR exon 20 insertion causes cell abnormalities as well [1]. In EGFR-tagged NSCLC cell lines, zipalertinib (TAS6417) (0–10 μM) suppresses both EGFR signaling and cell growth, regardless of whether the prevalent mutation T790M is present or not [2].
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| ln Vivo |
In an EGFR exon 20 insertion-driven tumor model, continuous tumor regression is produced in vivo by zipalertinib (TAS6417) (10–200 mg/kg). In NCI-H23 or NCI-H460 cells, TAS6417 inhibits bright EGFR in tumors but not WT EGFR in skin tissue [1]. Zipalertinib (TAS6417) has no effect on EGFR non-proliferative proliferation. At 20 mg/kg, zipalertinib (TAS6417) can significantly lower pEGFR and totally inhibit tumor growth. as a result, pAKT and pERK decreased at one hour, inhibition of inhibition was observed at six hours, and EGFR, ATK, and ERK phosphorylation was restored at the 24-hour mark [1]. TAS6417 (zipalertinib) 100 and 200 mg/kg/day
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| Cell Assay |
Apoptosis analysis [2]
Cell Types: PC 1]. -9, H1975, BID007, BID019, BEAS-2B cells. Tested Concentrations: 0-10μM. Incubation Duration: 24-48 hrs (hours). Experimental Results: Cell apoptosis was induced by inhibiting mutant EGFR. |
| Animal Protocol |
Animal/Disease Models: Mice implanted with NCI-H1975 EGFR D770_N771insSVD xenografts [1].
Doses: 50 and 100 mg/kg. Route of Administration: po (po (oral gavage)) one time/day for 14 days. Experimental Results: Demonstrated significant tumor growth inhibition with treatment/control (T/C) ratios of 51% and 19%, respectively. |
| References |
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| Additional Infomation |
Zipalertinib is an orally available selective inhibitor of a broad spectrum of epidermal growth factor receptor (EGFR) mutations, including EGFR exon 20 insertion mutations (EGFR Ex20ins; Ex20ins mutations), with potential antineoplastic activity. CLN-081 is also active against other EGFR mutations including exon 19 deletions (exon19del), L858R, and T790M, as well as the less common G719X, L861Q and S768I mutations. Upon administration, zipalertinib specifically and covalently binds to and inhibits a variety of EGFR mutations, with particularly high selectivity against EGFR Ex20ins, which prevents EGFR mutant-mediated signaling and leads to cell death in EGFR mutant-expressing tumor cells. Compared to some other EGFR inhibitors, CLN-081 may have therapeutic benefits in tumors with EGFR Ex20ins, as most EGFR mutant-selective inhibitors are not active against EGFR Ex20ins. 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 also 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.
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| Molecular Formula |
C23H20N6O
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| Molecular Weight |
396.4445
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| Exact Mass |
396.17
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| Elemental Analysis |
C, 69.68; H, 5.09; N, 21.20; O, 4.04
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| CAS # |
1661854-97-2
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| PubChem CID |
117918742
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| Appearance |
White to yellow solid powder
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| LogP |
2.3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
30
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| Complexity |
710
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=C[C@@H](CN2C1=C(C3=C(N=CN=C32)N)C4=CC5=CC=CC=C5N=C4)NC(=O)C=C
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| InChi Key |
MKCYPWYURWOKST-INIZCTEOSA-N
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| InChi Code |
InChI=1S/C23H20N6O/c1-3-18(30)28-16-8-13(2)21-19(15-9-14-6-4-5-7-17(14)25-10-15)20-22(24)26-12-27-23(20)29(21)11-16/h3-10,12,16H,1,11H2,2H3,(H,28,30)(H2,24,26,27)/t16-/m0/s1
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| Chemical Name |
(S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide
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| Synonyms |
Zipalertinib; TAS-6417; CLN-081; TAS6417; CLN081; TAS 6417;
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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: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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 : ~22.73 mg/mL (~57.34 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.25 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.
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 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: ≥ 2.08 mg/mL (5.25 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 20.8 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: ≥ 2.08 mg/mL (5.25 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 | 2.5224 mL | 12.6122 mL | 25.2245 mL | |
| 5 mM | 0.5045 mL | 2.5224 mL | 5.0449 mL | |
| 10 mM | 0.2522 mL | 1.2612 mL | 2.5224 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05973773 | RECRUITING | Drug:TAS6417 | Advanced or Metastatic NSCLS With Exon 20 Insertion Mutation |
Taiho Oncology, Inc. | 2023-06-30 | Phase 3 |
| NCT05967689 | RECRUITING | Drug: TAS6417 | Advanced or Metastatic NSCLC Harboring Epidermal Growth Factor Receptor(EGFR) Exon 20 Insertion(ex20ins) Mutations |
Taiho Oncology, Inc. | 2023-07-27 | Phase 2 |
| NCT04036682 | RECRUITING | Drug: CLN-081 | EGFR Exon 20 Mutation Non Small Cell Lung Cancer |
Cullinan Therapeutics Inc. | 2019-10-31 | Phase 1 Phase 2 |
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