title: Adenosine mimetics as inhibitors of NAD+-dependent histone deacetylases, from kinase to sirtuin inhibition.
abstract: NAD+-dependent histone deacetylases, sirtuins, cleave acetyl groups from lysines of histones and other proteins to regulate their activity. Identification of potent selective inhibitors would help to elucidate sirtuin biology and could lead to useful therapeutic agents. NAD+ has an adenosine moiety that is also present in the kinase cofactor ATP. Kinase inhibitors based upon adenosine mimesis may thus also target NAD+-dependent enzymes. We present a systematic approach using adenosine mimics from one cofactor class (kinase inhibitors) as a viable method to generate new lead structures in another cofactor class (sirtuin inhibitors). Our findings have broad implications for medicinal chemistry and specifically for sirtuin inhibitor design. Our results also raise a question as to whether selectivity profiling for kinase inhibitors should be limited to ATP-dependent targets.
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstrasse 25, 79104 Freiburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Trapp
authors.forename: Anne
authors.initials: A
authors.lastname: Jochum
authors.forename: Rene
authors.initials: R
authors.lastname: Meier
authors.forename: Laura
authors.initials: L
authors.lastname: Saunders
authors.forename: Brett
authors.initials: B
authors.lastname: Marshall
authors.forename: Conrad
authors.initials: C
authors.lastname: Kunick
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.forename: Peter
authors.initials: P
authors.lastname: Goekjian
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
mesh_terms: D000107:Acetylation; D000241:Adenosine / Q000737:chemistry*; D001665:Binding Sites; D045744:Cell Line, Tumor; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D047428:Protein Kinase Inhibitors; D014404:Tubulin; D037761:Sirtuins; D006655:Histone Deacetylases; D000241:Adenosine