ABSTRACT
The lysyl oxidase (LOX) family of extracellular proteins plays a vital role in catalyzing the formation of cross-links in fibrillar elastin and collagens leading to extracellular matrix (ECM) stabilization. These enzymes have also been implicated in tumor progression and metastatic disease and have thus become an attractive therapeutic target for many types of invasive cancers. Following our recently published work on the discovery of aminomethylenethiophenes (AMTs) as potent, orally bioavailable LOX/LOXL2 inhibitors, we report herein the discovery of a series of dual LOX/LOXL2 inhibitors, as well as a subseries of LOXL2-selective inhibitors, bearing an aminomethylenethiazole (AMTz) scaffold. Incorporation of a thiazole core leads to improved potency toward LOXL2 inhibition via an irreversible binding mode of inhibition. SAR studies have enabled the discovery of a predictive 3DQSAR model. Lead AMTz inhibitors exhibit improved pharmacokinetic properties and excellent antitumor efficacy, with significantly reduced tumor growth in a spontaneous breast cancer genetically engineered mouse model.
Subject(s)
Amino Acid Oxidoreductases/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Neoplasms/drug therapy , Protein-Lysine 6-Oxidase/antagonists & inhibitors , Thiazoles/pharmacology , Amination , Amino Acid Oxidoreductases/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Female , Humans , Mice , Mice, Inbred BALB C , Models, Molecular , Neoplasms/enzymology , Neoplasms/metabolism , Neoplasms/pathology , Protein-Lysine 6-Oxidase/metabolism , Rats , Sulfinic Acids/chemistry , Sulfinic Acids/pharmacokinetics , Sulfinic Acids/pharmacology , Sulfinic Acids/therapeutic use , Thiazoles/chemistry , Thiazoles/pharmacokinetics , Thiazoles/therapeutic useABSTRACT
Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase that cross-links collagens and elastin in the extracellular matrix and is a critical mediator of tumor growth and metastatic spread. LOX is a target for cancer therapy, and thus the search for therapeutic agents against LOX has been widely sought. We report herein the medicinal chemistry discovery of a series of LOX inhibitors bearing an aminomethylenethiophene (AMT) scaffold. High-throughput screening provided the initial hits. Structure-activity relationship (SAR) studies led to the discovery of AMT inhibitors with sub-micromolar half-maximal inhibitory concentrations (IC50) in a LOX enzyme activity assay. Further SAR optimization yielded the orally bioavailable LOX inhibitor CCT365623 with good anti-LOX potency, selectivity, pharmacokinetic properties, as well as anti-metastatic efficacy.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Protein-Lysine 6-Oxidase/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Biological Availability , Cell Line, Tumor , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Humans , Mice , Neoplasm Metastasis/drug therapy , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacokinetics , Thiophenes/pharmacology , Thiophenes/therapeutic useABSTRACT
The HIV-1 CA protein is an attractive therapeutic target for the development of new antivirals. An inter-protomer pocket within the hexamer configuration of the CA, which is a binding site for key host dependency factors, is an especially appealing region for small molecule targeting. Using a field-based pharmacophore derived from an inhibitor known to interact with this region, coupled to biochemical and biological assessment, we have identified a new compound that inhibits HIV-1 infection and that targets the assembled CA hexamer.
Subject(s)
Anti-HIV Agents/chemistry , Capsid Proteins/antagonists & inhibitors , HIV-1/metabolism , Anti-HIV Agents/metabolism , Anti-HIV Agents/pharmacology , Binding Sites , Capsid Proteins/metabolism , Cell Line , Drug Design , HIV-1/drug effects , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Protein Structure, Quaternary , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacologyABSTRACT
Demand remains for new inhibitors of HIV-1 replication and the inhibition of HIV-1 entry is an extremely attractive therapeutic approach. Using field-based bioisosteric replacements, we have further extended the chemotypes available for development in the HIV-1 entry inhibitor class. Moreover, using field-based disparity analysis of the compounds, 3D structure-activity relationships were derived that will be useful in the further development of these inhibitors towards clinical utility.
Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , HIV-1/drug effects , Virus Internalization/drug effects , Anti-HIV Agents/chemical synthesis , Hydrophobic and Hydrophilic Interactions , Models, Molecular , Molecular Structure , Static Electricity , Structure-Activity RelationshipABSTRACT
With the emergence of drug-resistant strains and the cumulative toxicities associated with current therapies, demand remains for new inhibitors of HIV-1 replication. The inhibition of HIV-1 entry is an attractive, yet underexploited therapeutic approach with implications for salvage and preexposure prophylactic regimens, as well as topical microbicides. Using the combination of a field-derived bioactive conformation template to perform virtual screening and iterative bioisosteric replacements, coupled with in silico predictions of absorption, distribution, metabolism, and excretion, we have identified new leads for HIV-1 entry inhibitors.
