ABSTRACT
The Aurora kinases are essential for cell mitosis, and the dysregulation of Aurora A and B have been linked to the etiology of human cancers. Investigational agents MLN8054 (8) and alisertib (MLN8237, 10) have been identified as high affinity, selective, orally bioavailable inhibitors of Aurora A that have advanced into human clinical trials. Alisertib (10) is currently being evaluated in multiple Phase II and III clinical trials in hematological malignancies and solid tumors.
ABSTRACT
The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin-proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Cyclopentanes/pharmacology , Enzyme Inhibitors/pharmacology , Neoplasms/drug therapy , Pyrimidines/pharmacology , Ubiquitin-Activating Enzymes/metabolism , Animals , Cell Line, Tumor , Cells, Cultured , Cullin Proteins/metabolism , Female , Humans , Mice , NEDD8 Protein , Proteasome Inhibitors , Transplantation, Heterologous , Ubiquitins/metabolismABSTRACT
Increased Aurora A expression occurs in a variety of human cancers and induces chromosomal abnormalities during mitosis associated with tumor initiation and progression. MLN8054 is a selective small-molecule Aurora A kinase inhibitor that has entered Phase I clinical trials for advanced solid tumors. MLN8054 inhibits recombinant Aurora A kinase activity in vitro and is selective for Aurora A over the family member Aurora B in cultured cells. MLN8054 treatment results in G(2)/M accumulation and spindle defects and inhibits proliferation in multiple cultured human tumor cells lines. Growth of human tumor xenografts in nude mice was dramatically inhibited after oral administration of MLN8054 at well tolerated doses. Moreover, the tumor growth inhibition was sustained after discontinuing MLN8054 treatment. In human tumor xenografts, MLN8054 induced mitotic accumulation and apoptosis, phenotypes consistent with inhibition of Aurora A. MLN8054 is a selective inhibitor of Aurora A kinase that robustly inhibits growth of human tumor xenografts and represents an attractive modality for therapeutic intervention of human cancers.
Subject(s)
Antineoplastic Agents/pharmacology , Benzazepines/pharmacology , Enzyme Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Administration, Oral , Animals , Aurora Kinase A , Aurora Kinase B , Aurora Kinases , Cell Line, Tumor , Disease Progression , Dose-Response Relationship, Drug , Female , Humans , Inhibitory Concentration 50 , Male , Mice , Mice, Nude , Neoplasm TransplantationABSTRACT
Strains within the genus Salinospora have been shown to produce complex natural products having antibiotic and antiproliferative activities. The biochemical basis for the cytotoxic effects of salinosporamide A has been linked to its ability to inhibit the proteasome. Synthetically accessible salinosporamide A (ML858) was used to determine its biochemical and biological activities and to compare its effects with those of bortezomib. ML858 and bortezomib show time- and concentration-dependent inhibition of the proteasome in vitro. However, unlike bortezomib, which is a reversible inhibitor, ML858 covalently binds to the proteasome, resulting in the irreversible inhibition of 20S proteasome activity. ML858 was equipotent to bortezomib in cell-based reporter stabilization assays, but due to intramolecular instability is less potent in long-term assays. ML858 failed to maintain levels of proteasome inhibition necessary to achieve efficacy in tumor models responsive to bortezomib. Our results show that ML858 and bortezomib exhibit different kinetic and pharmacologic profiles and suggest that additional characterization of ML858 is warranted before its therapeutic potential can be fully appreciated.
Subject(s)
Antineoplastic Agents/pharmacology , Boronic Acids/pharmacology , Lactones/pharmacology , Protease Inhibitors/pharmacology , Proteasome Inhibitors , Pyrazines/pharmacology , Pyrroles/pharmacology , Animals , Antineoplastic Agents/chemistry , Binding, Competitive , Boronic Acids/chemistry , Bortezomib , Drug Stability , Female , HT29 Cells , HeLa Cells , Humans , Lactones/chemistry , Mice , Mice, Nude , Mice, SCID , Protease Inhibitors/chemistry , Proteasome Endopeptidase Complex/metabolism , Pyrazines/chemistry , Pyrroles/chemistry , Xenograft Model Antitumor AssaysABSTRACT
Catalytic asymmetric ring-opening metathesis (AROM) provides an efficient method for the synthesis of a variety of optically enriched small organic molecules that cannot be easily prepared by alternative methods. The development of Mo-catalyzed AROM transformations that occur in tandem with ring-closing metathesis are described. The utility of the Mo-catalyzed AROM/ring-closing metathesis is demonstrated through an enantioselective approach to the synthesis of (+)-africanol.
Subject(s)
Alkenes/chemistry , Molybdenum/chemistry , Sesquiterpenes/chemical synthesis , Catalysis , Sesquiterpenes/chemistry , StereoisomerismABSTRACT
An enantiomerically pure Mo-based complex that bears an alkylimido ligand is prepared and characterized through NMR spectroscopy and X-ray analysis. Mo complex 4 is the only reported chiral alkylimido catalyst; all previous chiral complexes are arylimido systems. These studies show that the chiral Mo catalyst exists exclusively as the syn isomer and that it offers unique reactivity and selectivity profiles in asymmetric olefin metathesis.
