TAS6417

Catalog No.S8814 Synonyms: CLN-081, TPC-064

For research use only.

TAS6417 (CLN-081, TPC-064) is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. IC50 values ranges from 1.1 ± 0.1 to 8.0 ± 1.1 nmol/L.

TAS6417 Chemical Structure

CAS No. 1661854-97-2

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Biological Activity

Description TAS6417 (CLN-081, TPC-064) is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. IC50 values ranges from 1.1 ± 0.1 to 8.0 ± 1.1 nmol/L.
Targets
EGFR(d746-750/T790M) [1]
(Cell-free assay)
TXK [1]
(Cell-free assay)
EGFR(d746-750) [1]
(Cell-free assay)
EGFR L858R [1]
(Cell-free assay)
EGFR T790M/L858R [1]
(Cell-free assay)
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1.1 nM 1.1 nM 1.4 nM 1.9 nM 2 nM
In vitro

Of the 255 kinases tested, TAS6417 inhibits 25 kinases other than EGFR with IC50 values less than 1,000 nmol/L, which was 100 times higher than its IC50 value against WT EGFR. It inhibits only six kinases containing TXK, BMX, HER4, TEC, BTK, and JAK3, with IC50 values less than 10 times that against WT EGFR. TAS6417 inhibits proliferation of Ba/F3 cells driven by various EGFR exon 20 insertion mutations, with IC50 values ranging from 5.05 ± 1.33 nmol/L to 150 ± 53 nmol/L. It also suppresses 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 has no effect on EGFR-independent proliferation in NCI-H23 or NCI-H460 cells[1].

In vivo

TAS6417 causes persistent tumor regression in vivo in EGFR exon 20 insertion-driven tumor models. The tumor regression occurrs quickly after TAS6417 treatment and persists during the treatment period. Pharmacokinetic analysis reveals that the plasma concentration of TAS6417, administered at 50 and 100 mg/kg to mice, decreases rapidly in the first 4 hours. In contrast, although the effective doses in the rat model exhibit lower maximum plasma concentration (Cmax) values than those in the mouse model, the plasma concentrations tend to be more persistent, lasting up to 8 hours. TAS6417 inhibits mutant EGFR in tumors but not WT EGFR in skin tissues. It prolongs survival of animals bearing lung cancer[1].

Protocol (from reference)

Cell Research:

[1]

  • Cell lines: LXF 2478L cells and NCI-H1975 EGFR D770_N771insSVD cells
  • Concentrations: 0-1 μM
  • Incubation Time: 6 and 24 hours
  • Method:

    The cells are cultured with TAS6417 or afatinib and harvested 6 and 24 hours after treatment. Phosphorylation of EGFR-Tyr1068, AKT-Ser473, and ERK1/2-Thr202/Tyr204 and expression of BIM and cleaved PARP are determined using immunoblotting analysis.

Animal Research:

[1]

  • Animal Models: BALB/cAJcl-nu/nu nude mice with intrapulmonary NCI-H1975 EGFR D770_N771insSVD xenografts
  • Dosages: 100 mg/kg/day and 200 mg/kg/day
  • Administration: oral

Solubility (25°C)

In vitro

DMSO 79 mg/mL
(199.27 mM)
Water Insoluble
Ethanol '79 mg/mL

Chemical Information

Molecular Weight 396.44
Formula

C23H20N6O

CAS No. 1661854-97-2
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles CC1=CC(CN2C1=C(C3=C(N=CN=C32)N)C4=CC5=CC=CC=C5N=C4)NC(=O)C=C

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Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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