Zipalertinib

• CAS: 1661854-97-2
• Catalog Number: ACM1661854972
• Category: Inhibitors
• Molecular Weight: 396.45
• Molecular Formula: C23H20N6O
• 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.
• Synonyms: TAS6417; TAS-6417; TAS 6417; CLN-081; CLN081; CLN081; Zipalertinib
• IUPAC Name: (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide
• Canonical SMILES: NC1=C2C(N3C(C(C)=C[C@@H](C3)NC(C=C)=O)=C2C4=CC5=CC=CC=C5N=C4)=NC=N1
• InChI: 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
• InChI Key: MKCYPWYURWOKST-INIZCTEOSA-N
• Solubility: Soluble in DMSO
• Appearance: Solid powder
• Shelf Life: >3 years if stored properly
• Storage: Dry, dark and at 0-4 °C for short term (days to weeks) or -20 °C for long term (months to years).
• 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.
• Drug Formulation: This drug may be formulated in DMSO
• Elemental Analysis: C, 69.68; H, 5.09; N, 21.20; O, 4.04
• Exact Mass: 396.1699
• HS Tariff Code: 2934.99.9001
• 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/
• Shipping: 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.
• Stock Solution Storage: 0-4 °C for short term (days to weeks), or -20 °C for long term (months).