title: Bisubstrate analogue structure-activity relationships for p300 histone acetyltransferase inhibitors.
abstract: p300 and CBP are important histone acetyltransferases (HATs) that regulate gene expression and may be anti-cancer drug targets. Based on a previous lead compound, Lys-CoA, we have used solid phase synthesis to generate a series of 11 new analogues and evaluated these compounds as HAT inhibitors. Increased spacing between the CoA moiety and the lysyl moiety generally decreases inhibitory potency. We have found two substituted derivatives that show about 4-fold increased potency compared to the parent compound Lys-CoA. These structure-activity studies allow for a greater understanding of the optimal requirements for potent inhibition of HAT enzymes and pave the way for a novel class of anti-cancer therapeutics.
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Vatsala
authors.initials: V
authors.lastname: Sagar
authors.forename: Weiping
authors.initials: W
authors.lastname: Zheng
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003065:Coenzyme A / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051548:Histone Acetyltransferases; D008239:Lysine / Q000737:chemistry*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
chemical_list: D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D003065:Coenzyme A; D004791:Enzyme Inhibitors; D051548:Histone Acetyltransferases; D008239:Lysine; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor