title: Azide-alkyne cycloaddition affording enzymatically tunable bisubstrate based inhibitors of histone acetyltransferase PCAF.
abstract: A novel strategy to prepare bisubstrate based inhibitors for histone acetyltransferases is presented. To obtain these, azido peptides derived from histone H3 incorporating either a serine or a phosphoserine residue were connected to a propargyl coenzyme A derivative through copper catalyzed click chemistry. The resulting inhibitors were tested with therapeutically relevant acetyltransferase PCAF. Increased potency of the phosphoserine containing inhibitor was observed. The synthetic strategy presented may be used for developing bisubstrate based inhibitors against any acetyltransferase.
authors.affiliation: Medicinal Chemistry and Chemical Biology, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Ameijde
authors.affiliation: Medicinal Chemistry and Chemical Biology, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Addy P R
authors.initials: AP
authors.lastname: Zwiebel
authors.affiliation: PamGene International BV, Wolvenhoek 10, PO Box 1345, 5200 BJ 's Hertogenbosch, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Ruijtenbeek
authors.affiliation: Medicinal Chemistry and Chemical Biology, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; School of Chemistry, University of Glasgow, University Avenue, Glasgow G12 8QQ, United Kingdom. Electronic address: r.m.j.liskamp@uu.nl.
authors.forename: Rob M J
authors.initials: RM
authors.lastname: Liskamp
mesh_terms: D000480:Alkynes / Q000737:chemistry*; D001386:Azides / Q000737:chemistry*; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D000480:Alkynes; D001386:Azides; D004791:Enzyme Inhibitors; D051548:Histone Acetyltransferases; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
keywords: Bisubstrate based inhibitor; Enzyme inhibitor; Histone acetyltransferase; Posttranslational modification; Protein acetylation