PURPOSE: Histone deacetylase (HDAC) inhibitors have shown promising clinical 
activity in the treatment of hematologic malignancies, but their activity in 
solid tumor indications has been limited. Most HDAC inhibitors in clinical 
development only transiently induce histone acetylation in tumor tissue. Here, 
we sought to identify a "second-generation" class I HDAC inhibitor with 
prolonged pharmacodynamic response in vivo, to assess whether this results in 
superior antitumoral efficacy.
EXPERIMENTAL DESIGN: To identify novel HDAC inhibitors with superior 
pharmacodynamic properties, we developed a preclinical in vivo tumor model, in 
which tumor cells have been engineered to express fluorescent protein dependent 
on HDAC1 inhibition, thereby allowing noninvasive real-time evaluation of the 
tumor response to HDAC inhibitors.
RESULTS: In vivo pharmacodynamic analysis of 140 potent pyrimidyl-hydroxamic 
acid analogues resulted in the identification of JNJ-26481585. Once daily oral 
administration of JNJ-26481585 induced continuous histone H3 acetylation. The 
prolonged pharmacodynamic response translated into complete tumor growth 
inhibition in Ras mutant HCT116 colon carcinoma xenografts, whereas 
5-fluorouracil was less active. JNJ-26481585 also fully inhibited the growth of 
C170HM2 colorectal liver metastases, whereas again 5-fluorouracil/Leucovorin 
showed modest activity. Further characterization revealed that JNJ-26481585 is a 
pan-HDAC inhibitor with marked potency toward HDAC1 (IC(50), 0.16 nmol/L).
CONCLUSIONS: The potent antitumor activity as a single agent in preclinical 
models combined with its favorable pharmacodynamic profile makes JNJ-26481585 a 
promising "second-generation" HDAC inhibitor. The compound is currently in 
clinical studies, to evaluate its potential applicability in a broad spectrum of 
both solid and hematologic malignancies.