h3255

Afatinib Dimaleate (BIBW 2992MA2) is an orally bioavailable anilino-quinazoline derivative and inhibitor of the receptor tyrosine kinase (RTK) epidermal growth factor receptor (ErbB; EGFR) family, with antineoplastic activity.

Afatinib (BIBW 2992) is an irreversible inhibitor of the EGFR family (EGFR-wt, EGFR-L858R, EGFR-L858R/T790M, and HER2) with IC50s of 0.5 nM, 0.4 nM, 10 nM, and 14 nM, respectively.

Erlotinib (NSC-718781) is an EGFR inhibitor (IC50: 2 nM). It is used for the treatment of non-small cell lung cancer.

Gefitinib-based PROTAC 3, which connects an EGFR binding element to a VHL ligand via a linker, induces EGFR degradation with DC50s of 11.7 nM and 22.3 nM in HCC827 (exon 19 del) and H3255 (L858R mutation) cells, respectively[1].

WZ8040 is a novel mutant-selective irreversible EGFRT790M inhibitor, does not inhibit ERBB2 phosphorylation (T798I).

MS 154 is a potent and selective cereblon-recruiting Degrader (PROTAC®) of mutant epidermal growth factor receptor (EGFR), comprising a cereblon-binding moiety joined by a linker to gefitinib(Iressa). MS 154 decreases EGFR protein levels, inhibits downstream signaling in and inhibits proliferation of mutant EGFR-bearing lung cancer cells (DC50values are 11 and 25 nM in HCC-827 and H3255 cells, respectively; Dmax> 95% at 50 nM), but not in WT-EGFR-bearing ovarian and lung cancer cells lines. Bioavailable in mice following ip administration.

MS 39 is a potent Proteolysis Targeting Chimera (PROTAC) designed to degrade the Epidermal Growth Factor Receptor (EGFR). The molecule is composed of three structural motifs: an EGFR target ligand (red part), a VHL E3 ligase ligand (S,R,S)-AHPC (blue part), and an undecanedioic acid linker (black part). By facilitating the formation of a ternary complex between EGFR and the VHL E3 ubiquitin ligase, MS 39 triggers the polyubiquitination and subsequent proteasomal degradation of the receptor. MS 39 effectively reduces EGFR protein levels and inhibits downstream oncogenic signaling in HCC-827 and H3255 cell lines, leading to significant suppression of H3255 cancer cell proliferation.

EGFR-IN-151 (Compound 10) inhibits EGFR and its downstream signaling pathways ERK/STAT3. It effectively suppresses the proliferation of various lung cancer cells, with IC50 values of 11.7, 5.19, 7.32, and 1.53 μM for NCI-H1781, HCC827, NCI-H3255, and NCI-H1975, respectively. Additionally, EGFR-IN-151 hinders colony formation and cell migration in H1975, induces G1 phase cell cycle arrest, and triggers apoptosis in H1975 cells.

ZNL-0056 is an orally active ATP-competitive inhibitor that targets the EGFR ATP-binding site, specifically Cys797 and Cys775. It selectively inhibits EGFR and its downstream signaling in H3255 cells. ZNL-0056 is applicable for cancer research.

PROTACEGFRdegrader 12 (example 1) is a PROTAC degrader that selectively targets and degrades mutant EGFR, with minimal effect on EGFRWT. It demonstrates an IC50 of less than 50 nM against EGFRL858R-T790M (NCI-H1975 cells), EGFRL858R (NCI-H3255 cells), and EGFRL858R-T790M-L797S (NCI-H1975+CS cells).