Development of pyrazolone and isoxazol-5-one cambinol analogues as sirtuin inhibitors.
Sirtuins are a family of NAD(+)-dependent protein deacetylases that play critical roles in epigenetic regulation, stress responses, and cellular aging in eukaryotic cells. In an effort to identify small molecule inhibitors of sirtuins for potential use as chemotherapeutics as well as tools to modulate sirtuin activity, we previously identified a nonselective sirtuin inhibitor called cambinol (IC50 ≈ 50 μM for SIRT1 and SIRT2) with in vitro and in vivo antilymphoma activity. In the current study, we used saturation transfer difference (STD) NMR experiments with recombinant SIRT1 and 20 to map parts of the inhibitor that interacted with the protein. Our ongoing efforts to optimize cambinol analogues for potency and selectivity have resulted in the identification of isoform selective analogues: 17 with >7.8-fold selectivity for SIRT1, 24 with >15.4-fold selectivity for SIRT2, and 8 with 6.8- and 5.3-fold selectivity for SIRT3 versus SIRT1 and SIRT2, respectively. In vitro cytotoxicity studies with these compounds as well as EX527, a potent and selective SIRT1 inhibitor, suggest that antilymphoma activity of this compound class may be predominantly due to SIRT2 inhibition.
Clinical Research Division, Fred Hutchinson Cancer Research Center , 1100 Fairview Avenue North, Seattle, Washington 98109, United States.
Sumit S
SS
Mahajan
Michele
M
Scian
Smitha
S
Sripathy
Jeff
J
Posakony
Uyen
U
Lao
Taylor K
TK
Loe
Vid
V
Leko
Angel
A
Thalhofer
Aaron D
AD
Schuler
Antonio
A
Bedalov
Julian A
JA
Simon
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D055808:Drug Discovery; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D009281:Naphthalenes / Q000494:pharmacology*; D047069:Pyrazolones / Q000138:chemical synthesis* / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology*; D037761:Sirtuins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D007555:Isoxazoles; D009281:Naphthalenes; D047069:Pyrazolones; D011744:Pyrimidinones; C510718:cambinol; D037761:Sirtuins