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1.
Mol Cell ; 37(1): 102-11, 2010 Jan 15.
Article in English | MEDLINE | ID: mdl-20129059

ABSTRACT

The NEDD8-activating enzyme (NAE) initiates a protein homeostatic pathway essential for cancer cell growth and survival. MLN4924 is a selective inhibitor of NAE currently in clinical trials for the treatment of cancer. Here, we show that MLN4924 is a mechanism-based inhibitor of NAE and creates a covalent NEDD8-MLN4924 adduct catalyzed by the enzyme. The NEDD8-MLN4924 adduct resembles NEDD8 adenylate, the first intermediate in the NAE reaction cycle, but cannot be further utilized in subsequent intraenzyme reactions. The stability of the NEDD8-MLN4924 adduct within the NAE active site blocks enzyme activity, thereby accounting for the potent inhibition of the NEDD8 pathway by MLN4924. Importantly, we have determined that compounds resembling MLN4924 demonstrate the ability to form analogous adducts with other ubiquitin-like proteins (UBLs) catalyzed by their cognate-activating enzymes. These findings reveal insights into the mechanism of E1s and suggest a general strategy for selective inhibition of UBL conjugation pathways.


Subject(s)
Adenosine Monophosphate/metabolism , Cyclopentanes/metabolism , Enzyme Inhibitors/metabolism , Pyrimidines/metabolism , Ubiquitins/metabolism , Adenosine Monophosphate/chemistry , Binding Sites , Binding, Competitive , Cell Line, Tumor , Crystallography, X-Ray , Cyclopentanes/chemistry , Cyclopentanes/pharmacology , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , NEDD8 Protein , Protein Structure, Tertiary , Pyrimidines/chemistry , Pyrimidines/pharmacology , Ubiquitins/chemistry
2.
Nature ; 458(7239): 732-6, 2009 Apr 09.
Article in English | MEDLINE | ID: mdl-19360080

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/metabolism
3.
Bioorg Med Chem Lett ; 20(8): 2493-6, 2010 Apr 15.
Article in English | MEDLINE | ID: mdl-20304642

ABSTRACT

A series of triarylethanolamine inhibitors of the Kv1.5 potassium channel have been prepared and evaluated for their effects in vitro and in vivo. The structure-activity relationship (SAR) studies described herein led to the development of potent, selective and orally active inhibitors of Kv1.5.


Subject(s)
Ethanolamines/pharmacology , Potassium Channel Blockers/pharmacology , Potassium Channels, Voltage-Gated/antagonists & inhibitors , Animals , Dose-Response Relationship, Drug , Drug Discovery , Drug Evaluation, Preclinical , Ethanolamines/chemistry , Humans , Potassium Channel Blockers/chemistry , Structure-Activity Relationship
4.
J Med Chem ; 50(4): 807-19, 2007 Feb 22.
Article in English | MEDLINE | ID: mdl-17249648

ABSTRACT

The discovery of a novel series of NR2B subtype selective N-methyl-d-aspartate (NMDA) antagonists is reported. Initial optimization of a high-throughput screening lead afforded an aminopyridine derivative 13 with significant NR2B antagonist potency but limited selectivity over hERG-channel and other off-target activities. Further structure-activity studies on the aminoheterocycle moiety and optimization of the carbamate led to the highly potent 2-aminopyrimidine derivative 20j with a significantly improved off-target activity profile and oral bioavailability in multiple species coupled with good brain penetration. Compound 20j demonstrated efficacy in in vivo rodent models of antinociception, allodynia, and Parkinson's disease.


Subject(s)
Analgesics/chemical synthesis , Brain/metabolism , Pyrimidines/chemical synthesis , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Administration, Oral , Analgesics/pharmacokinetics , Analgesics/pharmacology , Animals , Antiparkinson Agents/chemical synthesis , Antiparkinson Agents/pharmacokinetics , Antiparkinson Agents/pharmacology , Biological Availability , Cell Line , Dogs , Female , Frontal Lobe/metabolism , Humans , Male , Pain Measurement , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
5.
ACS Med Chem Lett ; 6(6): 630-4, 2015 Jun 11.
Article in English | MEDLINE | ID: mdl-26101564

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.

6.
J Med Chem ; 47(7): 1602-4, 2004 Mar 25.
Article in English | MEDLINE | ID: mdl-15027849

ABSTRACT

The melanocortin 4 receptor (MC4R) plays an important role in body weight regulation and energy homeostasis. Administration of peptidic MC4R antagonists (usually by intracerebro ventricular injection) has been shown in the literature to increase body weight and/or food intake in several rodent models. We report here the identification of a novel nonpeptidic MC4R antagonist and its effects on tumor-induced weight loss in mice following peripheral administration.


Subject(s)
Benzamidines/chemical synthesis , Emaciation/drug therapy , Imidazoles/chemical synthesis , Neoplasms/complications , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Administration, Cutaneous , Animals , Benzamidines/chemistry , Benzamidines/pharmacology , Emaciation/etiology , Imidazoles/chemistry , Imidazoles/pharmacology , Mice , Mice, Inbred BALB C , Neoplasm Transplantation , Radioligand Assay , Structure-Activity Relationship , Transplantation, Heterologous
7.
Clin Cancer Res ; 17(24): 7614-24, 2011 Dec 15.
Article in English | MEDLINE | ID: mdl-22016509

ABSTRACT

PURPOSE: Small-molecule inhibitors of Aurora A (AAK) and B (ABK) kinases, which play important roles in mitosis, are currently being pursued in oncology clinical trials. We developed three novel assays to quantitatively measure biomarkers of AAK inhibition in vivo. Here, we describe preclinical characterization of alisertib (MLN8237), a selective AAK inhibitor, incorporating these novel pharmacodynamic assays. EXPERIMENTAL DESIGN: We investigated the selectivity of alisertib for AAK and ABK and studied the antitumor and antiproliferative activity of alisertib in vitro and in vivo. Novel assays were used to assess chromosome alignment and mitotic spindle bipolarity in human tumor xenografts using immunofluorescent detection of DNA and alpha-tubulin, respectively. In addition, 18F-3'-fluoro-3'-deoxy-l-thymidine positron emission tomography (FLT-PET) was used to noninvasively measure effects of alisertib on in vivo tumor cell proliferation. RESULTS: Alisertib inhibited AAK over ABK with a selectivity of more than 200-fold in cells and produced a dose-dependent decrease in bipolar and aligned chromosomes in the HCT-116 xenograft model, a phenotype consistent with AAK inhibition. Alisertib inhibited proliferation of human tumor cell lines in vitro and produced tumor growth inhibition in solid tumor xenograft models and regressions in in vivo lymphoma models. In addition, a dose of alisertib that caused tumor stasis, as measured by volume, resulted in a decrease in FLT uptake, suggesting that noninvasive imaging could provide value over traditional measurements of response. CONCLUSIONS: Alisertib is a selective and potent inhibitor of AAK. The novel methods of measuring Aurora A pathway inhibition and application of tumor imaging described here may be valuable for clinical evaluation of small-molecule inhibitors.


Subject(s)
Azepines/pharmacology , Neoplasms/drug therapy , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/pharmacology , Spindle Apparatus/drug effects , Animals , Aurora Kinase A , Aurora Kinases , Azepines/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dideoxynucleosides/pharmacokinetics , Female , Fluorine Radioisotopes , HCT116 Cells , HeLa Cells , Humans , Lymphoma/drug therapy , Lymphoma/metabolism , Lymphoma/pathology , Mice , Mice, Nude , Mice, SCID , Mitotic Index , Molecular Structure , Neoplasms/metabolism , Neoplasms/pathology , Phosphorylation/drug effects , Positron-Emission Tomography , Protein Serine-Threonine Kinases/metabolism , Pyrimidines/chemistry , Spindle Apparatus/metabolism , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
8.
Proc Natl Acad Sci U S A ; 104(10): 4106-11, 2007 Mar 06.
Article in English | MEDLINE | ID: mdl-17360485

ABSTRACT

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 Transplantation
11.
Bioorg Med Chem Lett ; 14(14): 3721-5, 2004 Jul 16.
Article in English | MEDLINE | ID: mdl-15203150

ABSTRACT

A novel series of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R) is reported. Members of this series have been identified, which exhibit sub-micromolar binding affinity for the MC4-R, functional potency <100nM, and good oral exposure in rat. Antagonists of the MC4-R are potentially useful in the therapeutic treatment of involuntary weight loss due to advanced age or disease (e.g. cancer or AIDS), an area of large, unmet medical need.


Subject(s)
Body Weight/drug effects , Imidazoles/chemical synthesis , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Animals , Binding Sites , Body Weight/physiology , Cells, Cultured , Imidazoles/pharmacology , Rats , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity Relationship
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