GSK9311 is an analog of GSK-6853, which is a benzimidazolone analog and a novel potent and highly selective inhibitor of the BRPF1 (Bromodomain and PHD Finger-containing) bromodomain with micromolar activity in a cellular target engagement assay, it shows excellent BRPF1 potency (pKd 9.5) and greater than 1600-fold selectivity over all other bromodomains tested. The BRPF protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. Screening GSK6853 against a panel of 48 unrelated assays reveals only off-target activities that are relatively weak compared to the BRPF1 potency. However, to minimize the chance of off-target effects , the recommended concentration is no higher than 1 μM in cell-based assays.
理化性质和储存条件
| Molecular Weight (MW) | 437.54 |
|---|
| Formula | C24H31N5O3 |
|---|
| CAS No. | 1923851-49-3(GSK9311) |
|---|
| Storage | -20℃ for 3 years in powder form |
|---|
| -80℃ for 2 years in solvent |
| Solubility (In vitro) | DMSO: 10 mM |
|---|
| Water: <1 mg/mL |
| Ethanol: <1 mg/mL |
| SMILES | O=C(N(CC)C1=C(N2[C@H](C)CNCC2)C=C(N3C)C(N(C)C3=O)=C1)C4=CC=CC=C4OC |
|---|
| Synonyms | GSK9311; GSK-9311; GSK 9311 |
|---|
实验参考方法
| In Vitro | In vitro activity: GSK-6853, a benzimidazolone analog, is a novel potent and highly selective inhibitor of the BRPF1 (Bromodomain and PHD Finger-containing) bromodomain with micromolar activity in a cellular target engagement assay, it shows excellent BRPF1 potency (pKd 9.5) and greater than 1600-fold selectivity over all other bromodomains tested. The BRPF protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. Screening GSK6853 against a panel of 48 unrelated assays reveals only off-target activities that are relatively weak compared to the BRPF1 potency. However, to minimize the chance of off-target effects , the recommended concentration is no higher than 1 μM in cell-based assays.
Kinase Assay: In previous study, GSK6853 was tested in the BROMOscan panel of bromodomain binding assays and the results showed that consistent with the previous findings, it showed excellent BRPF1 potency (pKd 9.5) and greater than 1600-fold selectivity over all other bromodomains tested. In addition, screening GSK6853 against a panel of 48 unrelated assays revealed only off-target activities that were relatively weak compared to its high BRPF1 potency.
Cell Assay: Screening GSK6853 against a panel of 48 unrelated assays reveals only off-target activities that are relatively weak compared to the BRPF1 potency. However, to minimize the chance of off-target effects , the recommended concentration is no higher than 1 μM in cell-based assays. |
|---|
| In Vivo | In male CD1 mouse, following IV administration (1 mg/kg), GSK6853 demonstrates a high blood clearance of 107 mL/min/kg, a moderate volume of distribution (5.5 L/kg) and a moderate terminal half-life of 1.7 h. Oral administration (PO, 3 mg/kg) achieves a moderate systemic exposure, with a Cmax of 42 ng/mL and Tmax of 1.5 h, resulting in a bioavailability of 22%. The intraperitoneal route of administration (IP, 3 mg/kg) reaches a Cmax of 469 ng/mL and Tmax of 0.25 h, resulting in a bioavailability of 85%. The results indicate that the IP route of administration would be suitable for dosing this molecule in potential PKPD models. |
|---|
| Animal model | CD1 mice |
|---|
| Formulation & Dosage | 1 mg/kg; i.p. or i.v. injection |
|---|
| References | ACS Med Chem Lett. 2016 May 9;7(6):552-7. |
|---|
m.cnreagent.com