JNJ-26481585, a novel "second-generation" oral histone deacetylase inhibitor, shows broad-spectrum preclinical antitumoral activity.
OBJECTIVE
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.


METHODS
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.
Arts
Janine
J
Ortho Biotech Oncology Research and Development, Clinical Pharmacology, Biostatistics, and Functional Genomics, Johnson & Johnson Pharmaceutical R. & D., Beerse, Belgium. jarts@its.jnj.com
King
Peter
P
Mariën
Ann
A
Floren
Wim
W
Beliën
Ann
A
Janssen
Lut
L
Pilatte
Isabelle
I
Roux
Bruno
B
Decrane
Laurence
L
Gilissen
Ron
R
Hickson
Ian
I
Vreys
Veronique
V
Cox
Eugene
E
Bol
Kees
K
Talloen
Willem
W
Goris
Ilse
I
Andries
Luc
L
Du Jardin
Marc
M
Janicot
Michel
M
Page
Martin
M
van Emelen
Kristof
K
Angibaud
Patrick
P
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000473:pathology; D005472:Fluorouracil / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006657:Histones / Q000737:chemistry; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000556:secondary; D008164:Luminescent Proteins / Q000737:chemistry; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D008164:Luminescent Proteins; C541788:quisinostat; D005472:Fluorouracil