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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Trapp J,Jochum A,Meier R,Saunders L,Marshall B,Kunick C,Verdin E,Goekjian P,Sippl W,Jung M

doi

10.1021/jm060118b

subject

Has Abstract

pub_date

2006-12-14 00:00:00

pages

7307-16

issue

25

eissn

0022-2623

issn

1520-4804

journal_volume

49

pub_type

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