Zipalertinib
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MedKoo CAT#: 207108

CAS#: 1661854-97-2

Description: Zipalertinib, also known as TAS6417, CLN-081, is a Novel EGFR Inhibitor Targeting Exon 20 Insertion Mutations. 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.


Chemical Structure

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Zipalertinib
CAS# 1661854-97-2

Theoretical Analysis

MedKoo Cat#: 207108
Name: Zipalertinib
CAS#: 1661854-97-2
Chemical Formula: C23H20N6O
Exact Mass: 396.1699
Molecular Weight: 396.454
Elemental Analysis: C, 69.68; H, 5.09; N, 21.20; O, 4.04

Price and Availability

Size Price Availability Quantity
10.0mg USD 90.0 Ready to ship
25.0mg USD 150.0 Ready to ship
50.0mg USD 250.0 Ready to ship
100.0mg USD 450.0 Ready to ship
200.0mg USD 750.0 Ready to ship
500.0mg USD 1650.0 Ready to ship
1.0g USD 2950.0 Ready to ship
2.0g USD 5250.0 Ready to ship
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Synonym: TAS6417; TAS-6417; TAS 6417; CLN-081; CLN081; CLN081; Zipalertinib;

IUPAC/Chemical Name: (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide

InChi Key: MKCYPWYURWOKST-INIZCTEOSA-N

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

SMILES Code: NC1=C2C(N3C(C(C)=C[C@@H](C3)NC(C=C)=O)=C2C4=CC5=CC=CC=C5N=C4)=NC=N1

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO

Shelf Life: >3 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: TAS6417 (CLN-081) is a highly effective pan-mutation-selective EGFR tyrosine kinase inhibitor with a unique scaffold fitting into the ATP-binding site of the EGFR hinge region, with IC50 values ranging from 1.1-8.0 nM.
In vitro activity: The effect of TAS6417 on tumor cell proliferation was investigated using a panel of seven human lung cancer cell lines expressing different EGFRs. . TAS6417 suppressed the growth of cells expressing exon 20 insertion mutations of the EGFR gene, with a GI50 value of 86.5 ± 28.5 nmol/L for LXF 2478L cells and 45.4 ± 2.6 nmol/L for NCI-H1975 EGFR D770_N771insSVD cells. TAS6417 also potently inhibited proliferation in other cell lines harboring activating mutations or acquired resistance mutations, with mean GI50 values of 1.92 ± 0.21 nmol/L to 7.12 ± 0.60 nmol/L. In contrast, the effect of TAS6417 on cell proliferation in normal human epidermal keratinocytes (NHEK-Neo), of which WT EGFR is implicated in the growth and survival. was moderate. Also, TAS6417 had no effect on EGFR-independent proliferation in NCI-H23 or NCI-H460 cells. Reference: Mol Cancer Ther. 2018 Aug;17(8):1648-1658. https://pubmed.ncbi.nlm.nih.gov/29748209/
In vivo activity: TAS6417 was further evaluated for its survival benefit in mice with intrapulmonary NCI-H1975 EGFR D770_N771insSVD xenografts. As a result of daily oral administration of TAS6417, dose-dependent prolonged survival was observed. TAS6417 administered at 100 and 200 mg/kg/day provided statistically significant prolongation of median survival compared to that of the control group, with ILS of 59% and 102%, respectively. The afatinib group exhibited no statistically significant ILS. Although the body weight of mice in the control group tended to increase by approximately 30 days after implantation, it decreased over time during the median survival period until animal death. In contrast, the TAS6417-treated group exhibited an increase in the body weight beyond 30 days. After this period, decreases in body weight associated with animal death were observed, just as in the control group. These data demonstrate not only the survival benefit of TAS6417 in mice with intrapulmonary xenograft tumors driven by EGFR exon 20 insertion mutations, but also the good tolerability of long-term daily administration. Reference: Mol Cancer Ther. 2018 Aug;17(8):1648-1658. https://pubmed.ncbi.nlm.nih.gov/29748209/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 20.0 50.44

Preparing Stock Solutions

The following data is based on the product molecular weight 396.454 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Udagawa H, Hasako S, Ohashi A, Fujioka R, Hakozaki Y, Shibuya M, Abe N, Komori T, Haruma T, Terasaka M, Fujita R, Hashimoto A, Funabashi K, Yasuda H, Miyadera K, Goto K, Costa DB, Kobayashi SS. TAS6417/CLN-081 Is a Pan-Mutation-Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant EGFR Mutations. Mol Cancer Res. 2019 Nov;17(11):2233-2243. doi: 10.1158/1541-7786.MCR-19-0419. Epub 2019 Aug 29. PMID: 31467113; PMCID: PMC6872223. 2. Hasako S, Terasaka M, Abe N, Uno T, Ohsawa H, Hashimoto A, Fujita R, Tanaka K, Okayama T, Wadhwa R, Miyadera K, Aoyagi Y, Yonekura K, Matsuo K. TAS6417, A Novel EGFR Inhibitor Targeting Exon 20 Insertion Mutations. Mol Cancer Ther. 2018 Aug;17(8):1648-1658. doi: 10.1158/1535-7163.MCT-17-1206. Epub 2018 May 10. PMID: 29748209.
In vitro protocol: 1. Udagawa H, Hasako S, Ohashi A, Fujioka R, Hakozaki Y, Shibuya M, Abe N, Komori T, Haruma T, Terasaka M, Fujita R, Hashimoto A, Funabashi K, Yasuda H, Miyadera K, Goto K, Costa DB, Kobayashi SS. TAS6417/CLN-081 Is a Pan-Mutation-Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant EGFR Mutations. Mol Cancer Res. 2019 Nov;17(11):2233-2243. doi: 10.1158/1541-7786.MCR-19-0419. Epub 2019 Aug 29. PMID: 31467113; PMCID: PMC6872223. 2. Hasako S, Terasaka M, Abe N, Uno T, Ohsawa H, Hashimoto A, Fujita R, Tanaka K, Okayama T, Wadhwa R, Miyadera K, Aoyagi Y, Yonekura K, Matsuo K. TAS6417, A Novel EGFR Inhibitor Targeting Exon 20 Insertion Mutations. Mol Cancer Ther. 2018 Aug;17(8):1648-1658. doi: 10.1158/1535-7163.MCT-17-1206. Epub 2018 May 10. PMID: 29748209.
In vivo protocol: 1. Udagawa H, Hasako S, Ohashi A, Fujioka R, Hakozaki Y, Shibuya M, Abe N, Komori T, Haruma T, Terasaka M, Fujita R, Hashimoto A, Funabashi K, Yasuda H, Miyadera K, Goto K, Costa DB, Kobayashi SS. TAS6417/CLN-081 Is a Pan-Mutation-Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant EGFR Mutations. Mol Cancer Res. 2019 Nov;17(11):2233-2243. doi: 10.1158/1541-7786.MCR-19-0419. Epub 2019 Aug 29. PMID: 31467113; PMCID: PMC6872223. 2. Hasako S, Terasaka M, Abe N, Uno T, Ohsawa H, Hashimoto A, Fujita R, Tanaka K, Okayama T, Wadhwa R, Miyadera K, Aoyagi Y, Yonekura K, Matsuo K. TAS6417, A Novel EGFR Inhibitor Targeting Exon 20 Insertion Mutations. Mol Cancer Ther. 2018 Aug;17(8):1648-1658. doi: 10.1158/1535-7163.MCT-17-1206. Epub 2018 May 10. PMID: 29748209.

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1: Hasako S, Terasaka M, Abe N, Uno T, Ohsawa H, Hashimoto A, Fujita R, Tanaka K,
Okayama T, Wadhwa R, Miyadera K, Aoyagi Y, Yonekura K, Matsuo K. TAS6417, A Novel
EGFR Inhibitor Targeting Exon 20 Insertion Mutations. Mol Cancer Ther. 2018
Aug;17(8):1648-1658. doi: 10.1158/1535-7163.MCT-17-1206. Epub 2018 May 10. PubMed
PMID: 29748209.