About A public-private partnership that supports the discovery of new medicines through open access research. Mission and Philosophy Partners Governance Collaborators Laboratories Key Achievements Strategic Alliances and Communications FAQs Sitemap Science TARGET ENABLING PACKAGES (TEPs) TISSUE PLATFORM PROTEIN STRUCTURES PUBLICATIONS CHEMICAL PROBES Donated chemical probes Biological probes Epigenetics Probes Collection Human Kinase Chemical Probe Program Probes against other protein classes RECOMBINANT ANTIBODIES Structure-guided Drug Discovery Coalition (SDDC) SDDC Publications CREATE ChemNET Research Program Trainees Open Access Learning Impact Faculty & Industry Participants Structural & Chemical Biology Bootcamp Events Structural Biology Programme Structural Parasitology Rare Diseases Genome Integrity and Neurodegeneration Growth Factor Signalling Integral Membrane Proteins Metabolic Enzymes Phosphorylation-Dependent Signalling Protein Kinases Ubiquitin Biology Chemical Biology Antibodies Protein Families Protein Methyltransferases Histone Deacetylases Histone Acetyltransferases Demethylases Bromodomains Methyl Lysine Readers Probe Development Screening Platforms Epigenetic Cell Assays Fragment Based Screening Informatics Medicinal Chemistry ChromoHub Phylogenetic Trees UbiHub Phylogenetic Trees Histone Tails Epigenetics Pocketome Technological Science Biotechnology Biophysics Screening Platforms Research Informatics Protein Crystallography Medicinal Chemistry Reagents & Resources Reagents Chemical Probes Antibodies SGC Vectors SGC Plasmids SGC Constructs Resources Structure Gallery Protein Production Protocols ChromoHub Phylogenetic Trees UbiHub Phylogenetic Trees Histone Tails Fragment Screening Crystal Forms Fragalysis MichaelaNGLo Technologies High Throughput Protein Crystallisation Lex Bubbling System Frapid People Global SGC Director Aled Edwards Susan McCormick Max Morgan Academic Collaborators Industrial/ SME collaborators Non-Scientists Toronto Cheryl Arrowsmith Dalia Barsyte-Lovejoy Peter J. Brown Jinrong Min Takis Prinos Matthieu Schapira Masoud Vedadi Levon Halabelian Biotechnology Crystallography Oxford Chas Bountra Paul Brennan Alex N. Bullock Nicola Burgess-Brown Liz Carpenter Jon Elkins Gillian Farnie Oleg Fedorov Panagis Filippakopoulos Opher Gileadi Kilian Huber Brian Marsden Udo Oppermann Frank von Delft Wyatt Yue UNICAMP Paulo Arruda Mario H. Bengtson Rafael M. Couñago Katlin B. Massirer UNC Tim Willson Bill Zuercher Carrow Wells Alison Axtman David Drewry Karolinska Michael Sundström Susanne Gräslund Louise Berg Per-Johan Jakobsson Frankfurt Stefan Knapp Susanne Müller-Knapp Alexandra Stolz Masato Akutsu News & Outreach News & Events SGC News Symposia & Workshops Blog Press Releases Public Events Public Engagement SGC Languages General Public Open Lab Notebooks Schools Media Patient Groups Governments TOronto Ubiquitin Club And Network (TOUCAN) Careers Tweets by thesgconline
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 and Cayman Chemical. 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.
