(3aR,6aR)-N-(4-((3-ethynylphenyl)amino)-7-methoxyquinazolin-6-yl)-1-methylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide

Uses

Theliatinib (Xiliertinib) is a potent, ATP-competitive, orally active and highly selective EGFR inhibitor with a Ki of 0.05 nM and an IC50 of 3 nM. Theliatinib has an IC50 of 22 nM for EGFR T790M/L858R mutant. Theliatinib shows >50-fold selectivity for EGFR than other kinases[1]. Theliatinib is a click chemistry reagent, it contains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups.

Biological Activity

Theliatinib (HMPL-309) is a potent EGFR inhibitor with a Ki value of 0.05 nM for EGFR and IC50 values of 3 nM and 22 nM for EGFR and EGFR T790M/L858R mutant, respectively. It is more than 50-fold selective for EGFR over 72 other kinases.

in vitro

Compared with erlotinib or gefitnib, theliatinib has stronger binding affinity to wild-type EGFR and is more difficult to be replaced by ATP, which makes theliatinib have better target binding effect, and the EGFR-activated tumors have stronger antitumor activity.

in vivo

Theliatinib has concentration-dependent antitumor activity in a series of patient-derived esophageal cancer xenograft models. But aberrant activation or genetic mutation of other targets such as PI3K and FGFR attenuates the antitumor activity of EGFR inhibitors, especially theliatinib.

target

IC 50

EGFR: 3 nM (IC₅₀); EGFR: 0.05 nM (Ki); EGFR (L858R/T790M): 22 nM (IC₅₀)

References

[1] Ren Y, et al. Anti-tumor efficacy of theliatinib in esophageal cancer patient-derived xenografts models with epidermal growth factor receptor (EGFR) overexpression and gene amplification. Oncotarget. 2017 Apr 19;8(31):50832-50844. DOI:10.18632/oncotarget.17243