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
BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance.
