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-Q9BZ95-F1-model_v6.cif)
Function
Histone methyltransferase. Preferentially dimethylates 'Lys-4' and 'Lys-27' of histone H3 forming H3K4me2 and H3K27me2. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation, while 'Lys-27' is a mark for transcriptional repression.
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
We next evaluated whether NSD3 depletion induced by XSY12 required proteasome activity. Co-treatment with the proteasome inhibitor MG132 markedly attenuated NSD3 loss (Figure 10C), indicating a proteasome-dependent degradation process rather than a simple reduction in protein expression.
Activity Data
Description
We next selected 12 HyT analogues and evaluated their ability to induce NSD3 degradation in HCC95 cells. Compounds were tested at 4,0.4,and 0.04 μM , followed by immunoblot analysis (Figures S8 and S9).Among the compounds examined, XSY12 produced the most pronounced, concentration-dependent depletion of NSD3 and showed clearly superior degradation efficiency relative to the other analogues. XSY12 was therefore prioritized for further characterization. Dose-response degradation studies showed that XSY12 achieved a DC50 =2.21± 0.37 μM with a Dmax of 80.2%（Figures 7E,G）
Description
We next selected 12 HyT analogues and evaluated their ability to induce NSD3 degradation in HCC95 cells. Compounds were tested at 4,0.4,and 0.04 μM , followed by immunoblot analysis (Figures S8 and S9).Among the compounds examined, XSY12 produced the most pronounced, concentration-dependent depletion of NSD3 and showed clearly superior degradation efficiency relative to the other analogues. XSY12 was therefore prioritized for further characterization. Dose-response degradation studies showed that XSY12 achieved a DC50 =2.21± 0.37 μM with a Dmax of 80.2%（Figures 7E,G）
Description
Most compounds showed measurable growth inhibition to varying extents (Table 5), with many analogues displaying greater potency in HCC95 cells. Several HyT conjugates were more active than SYC2 consistent with enhanced cellular efficacy upon hydrophobic-tag installation, Among the series, XSY12 was the most active compound, affording an IC50 = 0.21 ± 0.03 μM in HCC95 cells (Figure 7D),substantially improved relative to SYC2.
PK (Pharmacokinetics)
| Route | Dose | T1/2 | Tmax | Cmax | AUC | MRT | CL | F | Vd | Vz |
|---|---|---|---|---|---|---|---|---|---|---|
| IV | 1.0 mg/kg | 1.65±0.29 h | 0.08 | 1248.96±86.29 ng/ml | (0-t)528.71±27.44 h*ng/ml;(0-∞)536.16±27.22 h*ng/ml | Cl=1868.37±96.78 ml/h/kg. | ||||
| PO | 10.0 mg/kg | 4.45±0.65 h | 0.42±0.14 | 152.36±12.11 ng/ml | (0-t)380.25±167.92 h*ng/ml;(0-∞)386.01±170.67 h*ng/ml | 7.19±3.18 %. |
Disease Information
| Disease | ICD-11 | Source |
|---|---|---|
| Squamous cell cancer of lung | 2C25.2 | Cell Line Origin |
| Acute myeloid leukaemia | 2A60.3Z | Gene-Disease Association |
| Soft Tissue Sarcoma | XH4UM7 | Gene-Disease Association |