Adenosine mimetics as inhibitors of NAD+-dependent histone deacetylases, from kinase to sirtuin inhibition.
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.
Trapp
Johannes
J
Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstrasse 25, 79104 Freiburg, Germany.
Jochum
Anne
A
Meier
Rene
R
Saunders
Laura
L
Marshall
Brett
B
Kunick
Conrad
C
Verdin
Eric
E
Goekjian
Peter
P
Sippl
Wolfgang
W
Jung
Manfred
M
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
D056572:Histone Deacetylase Inhibitors; D047428:Protein Kinase Inhibitors; D014404:Tubulin; D037761:Sirtuins; D006655:Histone Deacetylases; D000241:Adenosine