A-485

A potent, selective and, cell and in vivo active p300/CBP catalytic inhibitor with IC50 of 9.8/2.6 nM; displays selectivity for p300/CBP over other HATs and histone methyltransferases in cells; dose-dependently decreases H3K27Ac in prostate adenocarcinoma PC-3 cells with EC50 of 73 nM; selectively inhibits proliferation in lineage-specific tumour types; inhibits the AR transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibits tumour growth in a castration-resistant xenograft model. (In Vitro) :A three-hour treatment of prostate adenocarcinoma PC-3 cells with A-485 results in a dose-dependent decrease in H3K27Ac, with a half maximal effective concentration (EC50) of 73 nM. Treatment with A-485 does not alter p300 or CBP protein levels.The broadest sensitivity is observed in haematological tumours, where A-485 exhibits potent activity in most multiple myeloma cell lines, and in a subset of acute myeloid leukaemia lines and non-Hodgkin’s lymphoma lines. A-485 induces a comparable decrease in H3K27Ac in all five prostate cancer cell lines. (In Vivo) :After tumours are established in SCID male mice, twice daily intraperitoneal injections of A-485 induce 54% tumour growth inhibition after 21 days of dosing (P<0.005 as compare to vehicle control) . In addition, in tumour-bearing animals, dosing with A-485 for seven days induces a decrease in the mRNA levels of MYC and the AR-dependent gene SLC45A3 at three hours post-dosing, and (for MYC) a decrease in the protein level, indicating that A-485 inhibits p300-mediated transcriptional activity in vivo. However, at 16 hours post-dosing on the seventh day, A-485 drug levels in the plasma and tumour are decreased as compare to 3 hours. A-485 induces a moderate 9% body weight loss, and the animals recover rapidly upon completion of the A-485 dosing regimen.