ABSTRACT
Pursuing our efforts in designing 5-pyrimidylhydroxamic acid anti-cancer agents, we have identified a new series of potent histone deacetylase (HDAC) inhibitors. These compounds exhibit enzymatic HDAC inhibiting properties with IC(50) values in the nanomolar range and inhibit tumor cell proliferation at similar levels. Good solubility, moderate bioavailability, and promising in vivo activity in xenograft model made this series of compounds interesting starting points to design new potent HDAC inhibitors.
Subject(s)
Antineoplastic Agents/chemistry , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylases/chemistry , Hydroxamic Acids/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation , Drug Design , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacology , Mice , Mice, Nude , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
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.
Subject(s)
Antineoplastic Agents/administration & dosage , Histone Deacetylase Inhibitors/administration & dosage , Hydroxamic Acids/administration & dosage , Neoplasms/drug therapy , Animals , Apoptosis , Cell Proliferation , Colonic Neoplasms/pathology , Fluorouracil/pharmacology , Histones/chemistry , Humans , Inhibitory Concentration 50 , Liver Neoplasms/secondary , Luminescent Proteins/chemistry , Male , Mice , Neoplasm Metastasis , Neoplasm TransplantationABSTRACT
Based on the structure of R115777 (tipifarnib, Zarnestra), a series of farnesyltransferase inhibitors have been synthesized by modification of the 2-quinolinone motif and transposition of the 4-chlorophenyl ring to the imidazole or its replacement by 5-membered rings. This has yielded a novel series of potent farnesyltransferase inhibitors.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase/antagonists & inhibitors , Quinolones/pharmacology , Antineoplastic Agents/chemistry , Enzyme Inhibitors/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Quinolones/chemistryABSTRACT
A series of pyrimidyl-5-hydroxamic acids was prepared for evaluation as inhibitors of histone deacetylase (HDAC). Amino-2-pyrimidinyl can be used as a linker to provide HDAC inhibitors of good enzymatic potency.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Cell Proliferation/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , HeLa Cells , Humans , Hydroxamic Acids/chemistry , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Molecular Structure , Pyrimidines/chemistry , Spectrometry, Mass, Electrospray IonizationABSTRACT
Replacement of the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA series by a 4-methyl-1,2,4-triazol-3-yl group gave us compounds with similar structure-activity relationship profiles showing that this triazole is potentially a good surrogate to imidazole for farnesyltransferase inhibition.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Quinolones/chemical synthesis , Quinolones/pharmacology , Triazoles/chemical synthesis , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Division/drug effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase , Heterocyclic Compounds/administration & dosage , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Kinetics , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Molecular Conformation , Quinolones/administration & dosage , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
A series of (4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)azoloquinolines and -quinazolines was prepared. These compounds displayed potent Farnesyl Protein Transferase inhibitory activity and tetrazolo[1,5-a]quinazolines are promising agents for oral in vivo inhibition.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Animals , Cell Division/drug effects , Drug Design , Enzyme Inhibitors/chemical synthesis , Farnesyltranstransferase , Kinetics , Molecular Conformation , Molecular Structure , Quinolones/chemical synthesis , Quinolones/pharmacology , Structure-Activity RelationshipABSTRACT
The evaluation of structure-activity relationships associated with the modification of the R115777 quinolinone ring moiety displaying potent in vitro inhibiting activity is described.
