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-P03372-F1-model_v6.cif)
Function
Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Maintains neuronal survival in response to ischemic reperfusion injury when in the presence of circulating estradiol (17-beta-estradiol/E2).
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
Finally, we investigated the possible mechanism of action of ERα degradation mediated by compound 16a(Fig.5E).To conduct these experiments, MCF-7 cells were pretreated with the proteasome inhibitor, MG132, the lysosomotrophic agent, chloroquine, or the partial SERD group, adamantly (HyT) prior to exposure to 16a, and then total ER expression was assessed as above. While MG132 reversed compound 16a degradation of ERα, chloroquine and HyT had no such effect. These results suggested that compound16a induces the degradation of Erαin cells via the 26S-proteasome,and the effect mainly attributes to the core structure of this compound family.
Activity Data
Description
As shown in Fig.5C and D, there sults of western blot indicated that compound 16a dramatically decreased the ERα protein level in a dose-and time dependent manner in MCF-7 cells and achieved near-complete ER depletion with a 1μM treatment. Gratifyingly, the progesterone receptor (PR), another steroid receptor was not degraded under this conditions (Fig.S2).These results indicated that target degradation by the 16a was selective for the ERα, and we did not see any effects on PR levels.
Description
Taken together, compound 16a possessed 9.6-fold stronger anti-proliferative ability on MCF-7 cells than that of MHO7 and showed the highest activity (IC50: 0.31-0.48 μM) against all tested cancer cell lines. Table1-Inhibitory activities of MHO7 analogues against the tested cancer cell lines
Description
The analysis of the SARs indicated that isopentenyl side chain of MHO7 was suitable for modification to improve its antitumor efficacy. Among them, compound 16a, bearing a 3-PEG adamantly moiety, was the most potent compound with a 10-fold improvement in potency compared with parent compound MHO7 against MCF-7 cancer cells with IC50 values of 0.41 μM. Moreover, compound 16a as novel SERDs also displayed excellent ERα degradation activity. Table1-Inhibitory activities of MHO7 analogues against the tested cancer cell lines
Description
Taken together, compound 16a possessed 9.6-fold stronger anti-proliferative ability on MCF-7 cells than that of MHO7 and showed the highest activity (IC50: 0.31-0.48 μM). Table1-Inhibitory activities of MHO7 analogues against the tested cancer cell lines
Disease Information
| Disease | ICD-11 | Source |
|---|---|---|
| Breast adenocarcinoma | 2C6Z | Cell Line Origin |
| Invasive breast carcinoma of no special type | 2C61.4 | Cell Line Origin |
| High grade ovarian serous adenocarcinoma | 2C73.03 | Cell Line Origin |
| Myocardial Infarction | BA41 | Gene-Disease Association |
| Coronary Artery Anomaly | LA8C | Gene-Disease Association |
| Endometrial Cancer | 2C76 | Gene-Disease Association |
| Hypogonadotropic Hypogonadism | 5A61.2 | Gene-Disease Association |
| Kallmann Syndrome | 5A61.0 | Gene-Disease Association |