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-O43924-F1-model_v6.cif)
Function
Promotes the release of prenylated target proteins from cellular membranes. Modulates the activity of prenylated or palmitoylated Ras family members by regulating their subcellular location. Required for normal ciliary targeting of farnesylated target proteins, such as INPP5E. Required for RAB28 localization to the cone cell outer segments in the retina (By similarity). Modulates the subcellular location of target proteins by acting as a GTP specific dissociation inhibitor (GDI). Increases the affinity of ARL3 for GTP by several orders of magnitude. Stabilizes ARL3-GTP by decreasing the nucleotide dissociation rate.
Degradation Pathway
Activity Data
Description
Given the potent PDEδ binding activity and degradation efficiency, the antiproliferative activities of the target compounds were investigated against two different KRAS mutant human colon cancer cells (SW480 and HCT116 cell lines) by a cell counting kit-8 (CCK8) assay (Table 1). Particularly, compound 17c (SW480 IC50 = 4.8 μM; HCT116 IC50 = 7.7 μM) exhibited the best antiproliferative activity. Importantly, the in vitro antitumor efficacies ofcompounds 17c were generally consistent with the degradation efficiency and the binding activity ofPDEδ.
Description
Given the potent PDEδ binding activity and degradation efficiency, the antiproliferative activities of the target compounds were investigated against two different KRAS mutant human colon cancer cells (SW480 and HCT116 cell lines) by a cell counting kit-8 (CCK8) assay (Table 1). Particularly, compound 17c (SW480 IC50 = 4.8 μM; HCT116 IC50 = 7.7 μM) exhibited the best antiproliferative activity. Importantly, the in vitro antitumor efficacies ofcompounds 17c were generally consistent with the degradation efficiency and the binding activity ofPDEδ.
Description
Moreover, its antiproliferative activity was further evaluated against MIAPACA-2 pancreatic cancer cells (Figure S1). The results indicated that the IC50 value of compound 17c was 17.5 μM, which was also significantly better than that of deltazinone (IC50 = 70.6 μM).
Description
Furthermore, the dose-dependent effect of compound 17c was explored (Figure 3C). The results indicated that compound 17c exhibited significant PDEδ degradation in a concentration-dependent manner and achieved aDC50 (concentration causing 50% protein degradation) value of 11.4 μM in SW480 cells for 24 h.
Description
Initially, a fluorescence polarization (FP) binding assay was performed to investigate the binding affinity of all targe. compounds with PDEδ using compound 1 as the positive control. As shown in Table 1, most of the target compounds exhibited good binding activity. Among them, two compounds, 17c and 17d, exhibited excellent binding activity, with Ki values of 26 and 29 nM, respectively.
Disease Information
| Disease | ICD-11 | Source |
|---|---|---|
| Colon adenocarcinoma | 2B90.Y | Cell Line Origin |
| Colon carcinoma | 2B90.Y | Cell Line Origin |
| Joubert syndrome | LD20.00 | Gene-Disease Association |
| Orofaciodigital syndrome type 6 | LD25.00 | Gene-Disease Association |
| Bardet-Biedl Syndrome | 5A61.0 | Gene-Disease Association |
| Retinal Disease | 9B7Z | Gene-Disease Association |
| Epilepsy | 8A6Z | Gene-Disease Association |