A-485

A-485 is a potent and selective catalytic inhibitor of p300/CBP with IC50s of 9.8 nM and 2.6 nM for p300 and CBP, respectively.

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. Treatment of the androgen-dependent LnCaP-FGC cell line with A-485 attenuates dihydrotestosterone (DHT) stimulated prostate-specific antigen (PSA) expression[1].

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 (PMYC 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[1].

[1]. Lasko LM, et al. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. Nature. 2017 Oct 5;550(7674):128-132.