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.
Kinzel
Olaf
O
IRBM/Merck Research Laboratories, Pomezia, Italy. olaf_kinzel@merck.com
Llauger-Bufi
Laura
L
Pescatore
Giovanna
G
Rowley
Michael
M
Schultz-Fademrecht
Carsten
C
Monteagudo
Edith
E
Fonsi
Massimiliano
M
Gonzalez Paz
Odalys
O
Fiore
Fabrizio
F
Steinkühler
Christian
C
Jones
Philip
P
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