A 485 is a potent and selective p300/CREB-binding protein (CBP) HAT domain inhibitor with IC50 of 2.6 and 9.8 nM for the CBP-bromodomain HAT-C/H3 (BHC) and p300-BHC domains, respectively.
The histone acetyltransferase paralogs p300 and CBP (p300/CBP) are transcriptional co-activators, essential for a multitude of cellular events and the pathogenesis of multiple human diseases. A-485 is a potent, selective, drug-like p300/CBP catalytic inhibitor. It inhibited the activity of the p300-BHC (bromodomain-HAT-C/H3) domain and CBP-BHC with IC50 values of 9.8nM and 2.6nM, respectively. A-485 bound to p300-HAT with a KD of 15±1nM. Treatment of prostate adenocarcinoma PC-3 cells with A-485 for 3h resulted in a concentration-dependent reduction in H3K27Ac with an EC50 of 73nM. In androgen-dependent LnCaP-FGC cell line, treatment with A-485 for 7 and 24h decreased DHT-stimulated PSA expression more potently compared to AR antagonist enzalutamide. A-485 also downregulated 40% of DHT-responsive genes in androgen-depleted 22Rv1 cells. In male SCID mice, twice daily intraperitoneal injection of A-485 (twice per day) resulted in 54% tumor growth inhibition after 21 days of dosing as compared to vehicle-treated controls. Also, treatment with A-485 in tumor-bearing animals for 7 days decreased the mRNA levels of AR-dependent gene, SLC45A3, and c-Myc, at 3h after dosing[1].
作用机制
A-485 is a potent, selective p300/CBP inhibitor that binds to the catalytic active site of p300 and inhibits p300/CBP in an acetyl-CoA competitive manner. The methyl-urea of A-485 is inserted through the L1 loop where two hydrogen bonds are formed[1].
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