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A public-private partnership that supports the discovery of new medicines through open access research.
A-485 A chemical probe for p300/CBPThis probe is available to purchase from Tocris, Cayman Chemical and Sigma. The control may be requested by clicking here. For any inquiries please contact proberequests@thesgc.org.group newOverview A-485 A-486 Abbvie has developed a potent acetyl-CoA competitive histone acetyltransferase (HAT) inhibitor of p300/CBP and has donated A-485 and its control A-486 to the SGC probe collection, following review of published data along SGC probe guidelines. A-485 is a potent and selective HAT inhibitor of p300/CBP in vitro with an IC50 of 10 nM in a p300 TR-FRET assay and 3 nM in a CBP TR-FRET assay with selectivity > 1000-fold over closely related HATs. SPR data indicates potent binding to p300 (KD=15 nM). In PC-3 cells A-485 reduces H3K27ac with IC50 of 73 nM while not affecting H3K9ac levels. Inhibition of cellular proliferation is observed in several cancer cell types, most notably AR+ prostate, multiple myeloma, and NHL. A-486 is a suitable control with 1000-fold higher IC50 in the p300 TR-FRET assay. Properties A-485 A-486 (Negative Control) Physical and chemical properties for A-485 Molecular weight 536.2 Molecular formula C25H24F4N4O5 IUPAC name N-(4-Fluorobenzyl)-2-{(1R)-5-[(methylcarbamoyl)amino]-2',4'-dioxo-2,3-dihydro-3'H-spiro[indene-1,5'-[1,3]oxazolidin]-3'-yl}-N-[(2S)-1,1,1-trifluoro-2-propanyl]acetamide MollogP 3.407 PSA 86.47 No. of chiral centres 2 No. of rotatable bonds 10 No. of hydrogen bond acceptors 9 No. of hydrogen bond donors 2 Physical and chemical properties for A-486 (Negative Control) Molecular weight 536.2 Molecular formula C25H24F4N4O5 MollogP 3.407 PSA 86.47 No. of chiral centres 2 No. of rotatable bonds 10 No. of hydrogen bond acceptors 9 No. of hydrogen bond donors 2 SMILES: A-485: C[C@@H](C(F)(F)F)N(Cc1ccc(cc1)F)C(CN1C([C@]2(CCc3cc(ccc23)NC(NC)=O)OC1=O)=O)=O A-486: C[C@@H](C(F)(F)F)N(Cc1ccc(cc1)F)C(CN1C([C@]2(CCc3ccc(cc23)NC(NC)=O)OC1=O)=O)=O InChI: A-485: InChI=1S/C25H24F4N4O5/c1-14(25(27,28)29)32(12-15-3-5-17(26)6-4-15)20(34)13-33-21(35)24(38-23(33)37)10-9-16-11-18(7-8-19(16)24)31-22(36)30-2/h3-8,11,14H,9-10,12-13H2,1-2H3,(H2,30,31,36)/t14-,24+/m0/s1 A-486: InChI=1S/C25H24F4N4O5/c1-14(25(27,28)29)32(12-15-3-6-17(26)7-4-15)20(34)13-33-21(35)24(38-23(33)37)10-9-16-5-8-18(11-19(16)24)31-22(36)30-2/h3-8,11,14H,9-10,12-13H2,1-2H3,(H2,30,31,36)/t14-,24+/m0/s1 InChIKey: A-485: VRVJKILQRBSEAG-LFPIHBKWSA-N A-486: MTTJOZOOUCZVHO-LFPIHBKWSA-N Cell-based Assay Data Analysis of high content microscopy shows that A-485 (but not A-486) decreases H3K27Ac (open squares), but not H3K9Ac (closed squares) levels after three hours of treatment in PC-3 cells. Error bars represent the s.d. of n = 3 independent biological replicates A-485 selectively inhibits production of p300 acetylation products H3K27Ac and H3K18Ac after three hours of treatment in PC-3 cells (n = 2). Co-crystal structures Please wait whilst the interactive viewer is loaded! Main features 1. Overall structure of Δp300 HAT domain with A-485 2. Overlay of Lys-CoA structure indicating A-485 binds in CoA site 3. Shape of A-485 binding pocket 4. Key interactions of the binding of A-485 to Δp300 HAT domain References Lasko, L., Jakob, C., Edalji, R., Qiu, W., Montgomery, D., & Digiammarino, E. et al. (2017). Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. Nature, 550, 128-132. Weinert BT, Narita T, Satpathy S, Srinivasan B, Hansen BK, Schölz C, et al. (2018) Time-Resolved Analysis Reveals Rapid Dynamics and Broad Scope of the CBP/p300 Acetylome. Cell 174: 1-14.
