Discovery of a potent class I selective ketone histone deacetylase inhibitor with antitumor activity in vivo and optimized pharmacokinetic properties.
The optimization of a potent, class I selective ketone HDAC inhibitor is shown. It possesses optimized pharmacokinetic properties in preclinical species, has a clean off-target profile, and is negative in a microbial mutagenicity (Ames) test. In a mouse xenograft model it shows efficacy comparable to that of vorinostat at a 10-fold reduced dose.
IRBM/Merck Research Laboratories, Pomezia, Italy. olaf_kinzel@merck.com
Olaf
O
Kinzel
Laura
L
Llauger-Bufi
Giovanna
G
Pescatore
Michael
M
Rowley
Carsten
C
Schultz-Fademrecht
Edith
E
Monteagudo
Massimiliano
M
Fonsi
Odalys
O
Gonzalez Paz
Fabrizio
F
Fiore
Christian
C
Steinkühler
Philip
P
Jones
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D051379:Mice; D011804:Quinolines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011804:Quinolines