Basic Information
Remarks
Chemical Identifiers
Basic Properties
Lipinski RO5
Hydrophobic Tag Properties
Mechanism of Action
POI (Protein of Interest)
Amino Acid Sequence
3D Structure (/structures/AF-P00533-F1-model_v6.cif)
Function
Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, AREG, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May also activate the NF-kappa-B signaling cascade. Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin. Positively regulates cell migration via interaction with CCDC88A/GIV which retains EGFR at the cell membrane following ligand stimulation, promoting EGFR signaling which triggers cell migration. Plays a role in enhancing learning and memory performance (By similarity). Plays a role in mammalian pain signaling (long-lasting hypersensitivity) (By similarity). Isoform 2 may act as an antagonist of EGF action. (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry. Mediates HCV entry by promoting the formation of the CD81-CLDN1 receptor complexes that are essential for HCV entry and by enhancing membrane fusion of cells expressing HCV envelope glycoproteins.
Degradation Pathway
Mechanism
The ubiquitin-proteasome pathway (UPP) constitutes the principal pathway for protein degradation in eukaryotic cells, mediating the breakdown of target proteins through ubiquitin tagging and subsequent proteasomal degradation. In an ATP-dependent manner, the ubiquitin-activating enzyme (E1) activates ubiquitin (Ub) and conjugates it to a ubiquitin-conjugating enzyme (E2). E3 ligase subsequently catalyzes the transfer of Ub to the target protein, leading to the formation of a polyubiquitin chain that completes the ubiquitination mark. The 19S regulatory particle of the 26S proteasome recognizes this ubiquitination signal and, after deubiquitination, mediates the ATP-dependent delivery of the substrate into the 20S proteasome for degradation.
Description
To investigate the degradation pathway of EGFR induced by compound7, cells were pretreated with MG-132 (a proteasome inhibitor), 3-MA (a lysosome inhibitor), and PYR 41 (an E1 ligase inhibitor) in vitro. Compared with the 3-MA treatment group, pretreatment withMG-132 and PYR-41 markedly attenuated EGFR degradation (Figure 2E), implicating the UPS pathway in compound 7-mediated EGFR degrdation. The results of further experiments revealed that compound 7 treatment significantly reduced the half-time of EGFR in the presence of Cycloheximide (CHX, a protein synthesis inhibitor) (Figure 2F,G) and increased its ubiquitination levels (Figure 2H), supporting USP-mediated degradation.
Activity Data
Description
To assess the impact of compound 7 on EGFR degradation, Western blotting was conducted on PC-9and HCC-827 cells, which were subjected to serum starvation for 8 h and then treated with varying concentrations and durations of compound 7. Results indicated that compound 7 effectively induced a dose-dependent decrease in mutant EGFR levels(DC50=1.42 and 0.75 μM for EGFR respectively; Figure 2A,B)and time-dependent reduction(Figure 2C)
Description
To assess the impact of compound 7 on EGFR degradation, Western blotting was conducted on PC-9and HCC-827 cells, which were subjected to serum starvation for 8 h and then treated with varying concentrations and durations of compound 7. Results indicated that compound 7 effectively induced a dose-dependent decrease in mutant EGFR levels(DC50=1.42 and 0.75 μM for EGFR respectively; Figure 2A,B)and time-dependent reduction(Figure 2C).
Description
Initially, the IC50 values for compound 7 against two NSCLC cell lines, HCC-827 and PC-9, were determined using a CCK-8 cell viability assay, revealing its notable cytotoxicity (IC50 = 0.09 and 0.34 μM, respectively).
Description
Initially, the IC50 values for compound 7 against two NSCLC cell lines, HCC-827 and PC-9, were determined using a CCK-8 cell viability assay, revealing its notable cytotoxicity (IC50 = 0.09 and 0.34 μM, respectively).
PK (Pharmacokinetics)
| Route | Dose | T1/2 | Tmax | Cmax | AUC | MRT | CL | F | Vd | Vz |
|---|---|---|---|---|---|---|---|---|---|---|
| I.V. | 1 mg/kg | 2.18±0.02 h | 0.08±0.01 h | 2212.85±149.32 ng/mL | (0-t) 2164.76±184.92 ng/mL | (0-t) 2.72±0.24 h | NA | NA | NA | NA |
| P.O. | 10 mg/kg | 1.29±0.67 h | 1.00±0.01 h | 682.69±67.86 ng/mL | (0-t) 1876.65±196.28 h*ng/mL | (0-t) 2.57±0.68 h | NA | 8.67% | NA | NA |
Disease Information
| Disease | ICD-11 | Source |
|---|---|---|
| lung adenocarcinoma | 2C25.0 | Cell Line Origin |
| Giant cell glioblastoma | 2A00.00 | Gene-Disease Association |
| Glioblastoma | 2A00.00 | Gene-Disease Association |
| Gliosarcoma | 2A00.00 | Gene-Disease Association |
| Adenocarcinoma | 2D40 | Gene-Disease Association |
| Ewing Sarcoma | XH8KJ8 | Gene-Disease Association |
| Sarcoma | 2B5F.3 | Gene-Disease Association |
| Ovarian Cancer | 2C73 | Gene-Disease Association |