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-Q96LA8-F1-model_v6.cif)
Function
Arginine methyltransferase that can catalyze the formation of both omega-N monomethylarginine (MMA) and asymmetrical dimethylarginine (aDMA), with a strong preference for the formation of aDMA. Preferentially methylates arginyl residues present in a glycine and arginine-rich domain and displays preference for monomethylated substrates. Specifically mediates the asymmetric dimethylation of histone H3 'Arg-2' to form H3R2me2a. H3R2me2a represents a specific tag for epigenetic transcriptional repression and is mutually exclusive with methylation on histone H3 'Lys-4' (H3K4me2 and H3K4me3). Acts as a transcriptional repressor of various genes such as HOXA2, THBS1 and TP53. Repression of TP53 blocks cellular senescence (By similarity). Also methylates histone H2A and H4 'Arg-3' (H2AR3me and H4R3me, respectively). Acts as a regulator of DNA base excision during DNA repair by mediating the methylation of DNA polymerase beta (POLB), leading to the stimulation of its polymerase activity by enhancing DNA binding and processivity. Methylates HMGA1. Regulates alternative splicing events. Acts as a transcriptional coactivator of a number of steroid hormone receptors including ESR1, ESR2, PGR and NR3C1. Promotes fasting-induced transcriptional activation of the gluconeogenic program through methylation of the CRTC2 transcription coactivator (By similarity). May play a role in innate immunity against HIV-1 in case of infection by methylating and impairing the function of various HIV-1 proteins such as Tat, Rev and Nucleocapsid protein p7 (NC). Methylates GPS2, protecting GPS2 from ubiquitination and degradation (By similarity). Methylates SIRT7, inhibiting SIRT7 histone deacetylase activity and promoting mitochondria biogenesis.
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 further investigate the potential mechanism of the PRMT6 degraded by SKLB-0124, we co-treated MDA-MB-435 cells with the proteasome inhibitor MG132 and lysosomal inhibitor chloroquine together with SKLB-0124 and performed immunoblotting assays. As shown in Fig. 7A and 7B, MG132 reversed the degradation of SKLB-0124 by inhibiting the cellular UPS pathway, while treatment with chloroquine (lysosomal inhibitor) did not affect the degradation of PRMT6. These findings demonstrated that the proteasome plays a central role in the HyT-mediated degradation mechanism
Activity Data
Description
We further evaluated the dose–response relationship of SKLB-0124 on PRMT6 degradation after treating HCC827 cells and MDA-MB-435 cells with various concentrations of SKLB-0124. HCC827 cells and MDA-MB-435 cells were treated with SKLB-0124 for 6 days, as demonstrated in Fig. 4A and 4B, SKLB-0124 induced a significant reduction of PRMT6 protein expression in a dose-dependent manner, with DC50 and Dmax values of 15.4 μM and 64.8 % for HCC827 cells and 14.6 μM and 70.4 %, respectively, for MDA-MB-435 cells.
Description
We further evaluated the dose–response relationship of SKLB-0124 on PRMT6 degradation after treating HCC827 cells and MDA-MB-435 cells with various concentrations of SKLB-0124. HCC827 cells and MDA-MB-435 cells were treated with SKLB-0124 for 6 days, as demonstrated in Fig. 4A and 4B, SKLB-0124 induced a significant reduction of PRMT6 protein expression in a dose-dependent manner, with DC50 and Dmax values of 15.4 μM and 64.8 % for HCC827 cells and 14.6 μM and 70.4 %, respectively, for MDA-MB-435 cells.
Description
We further evaluated the dose–response relationship of SKLB-0124 on PRMT6 degradation after treating HCC827 cells and MDA-MB-435 cells with various concentrations of SKLB-0124. HCC827 cells and MDA-MB-435 cells were treated with SKLB-0124 for 6 days, as demonstrated in Fig. 4A and 4B, SKLB-0124 induced a significant reduction of PRMT6 protein expression in a dose-dependent manner, with DC50 and Dmax values of 15.4 μM and 64.8 % for HCC827 cells and 14.6 μM and 70.4 %, respectively, for MDA-MB-435 cells.
Description
We further evaluated the dose–response relationship of SKLB-0124 on PRMT6 degradation after treating HCC827 cells and MDA-MB-435 cells with various concentrations of SKLB-0124. HCC827 cells and MDA-MB-435 cells were treated with SKLB-0124 for 6 days, as demonstrated in Fig. 4A and 4B, SKLB-0124 induced a significant reduction of PRMT6 protein expression in a dose-dependent manner, with DC50 and Dmax values of 15.4 μM and 64.8 % for HCC827 cells and 14.6 μM and 70.4 %, respectively, for MDA-MB-435 cells
Description
We speculated that the same effect would occur after methylation at the same position in SKLB-0124, so we designed and synthesized the negative control compound SKLB-0266 (Fig. 6A). The enzyme activity data showed that the IC50 value of SKLB-0124 on PRMT6 was 1616.547 nM (Fig. 6B). After the methylation of NH, the inhibitory activity of the negative control compound SKLB-0266 on PRMT6 was almost completely lost (Fig. 6C).
Description
To evaluate the antiproliferative activity of SKLB-0124 on these two cancer cell lines, MDA-MB-435 and HCC827 cell were treated with graded concentrations of SKLB-0124 for 6 days. As shown in Fig. 10A and 10B, the IC 50 values of SKLB-0124 against MDA-MB-435 and HCC827 cells were 5.68 μM and 6.66 μM
Description
To evaluate the antiproliferative activity of SKLB-0124 on these two cancer cell lines, MDA-MB-435 and HCC827 cell were treated with graded concentrations of SKLB-0124 for 6 days. As shown in Fig. 10A and 10B, the IC 50 values of SKLB-0124 against MDA-MB-435 and HCC827 cells were 5.68 μM and 6.66 μM
PK (Pharmacokinetics)
| Route | Dose | T1/2 | Tmax | Cmax | AUC | MRT | CL | F | Vd | Vz |
|---|---|---|---|---|---|---|---|---|---|---|
| I.V. | 1 mg/kg | 3.12 h | 0.033 h | 559 ng/mL | (0-t)88.1 h*ng/mL (0-∞)113 h*ng/mL | 2.09 h |
Disease Information
| Disease | ICD-11 | Source |
|---|---|---|
| Lung adenocarcinoma | 2C25.0 | Cell Line Origin |
| Amelanotic melanoma | XH3TK1 | Cell Line Origin |
| Male Infertility | GB04 | Gene-Disease Association |
| Azoospermia | G804.0 | Gene-Disease Association |
| Spinal Muscular Atrophy | 8B61 | Gene-Disease Association |
| Autism Spectrum Disorder | 6A02 | Gene-Disease Association |
| Acute Myeloid Leukemia | 2A60.3Z | Gene-Disease Association |