RÉSUMÉ
We describe the successful application of a novel approach for generating dimeric Myc inhibitors by modifying and reversibly linking two previously described small molecules. We synthesized two directed libraries of monomers, each comprised of a ligand, a connector, and a bioorthogonal linker element, to identify the optimal dimer configuration required to inhibit Myc. We identified combinations of monomers, termed self-assembling dimeric inhibitors, which displayed synergistic inhibition of Myc-dependent cell growth. We confirmed that these dimeric inhibitors directly bind to Myc blocking its interaction with Max and affect transcription of MYC dependent genes. Control combinations that are unable to form a dimer do not show any synergistic effects in these assays. Collectively, these data validate our new approach to generate more potent and selective inhibitors of Myc by self-assembly from smaller, lower affinity components. This approach provides an opportunity for developing novel therapeutics against Myc and other challenging protein:protein interaction (PPI) target classes.
Sujet(s)
Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines/génétique , Prolifération cellulaire/effets des médicaments et des substances chimiques , Tumeurs/génétique , Protéines proto-oncogènes c-myc/biosynthèse , Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines/biosynthèse , Lignée cellulaire tumorale , Conception de médicament , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Glycols/composition chimique , Humains , Ligands , Tumeurs/traitement médicamenteux , Cartes d'interactions protéiques/effets des médicaments et des substances chimiques , Protéines proto-oncogènes c-myc/antagonistes et inhibiteurs , Protéines proto-oncogènes c-myc/génétique , ARN messager/biosynthèse , Bibliothèques de petites molécules/administration et posologieRÉSUMÉ
This digest covers some of the most relevant progress in malaria drug discovery published between 2010 and 2012. There is an urgent need to develop new antimalarial drugs. Such drugs can target the blood stage of the disease to alleviate the symptoms, the liver stage to prevent relapses, and the transmission stage to protect other humans. The pipeline for the blood stage is becoming robust, but this should not be a source of complacency, as the current therapies set a high standard. Drug discovery efforts directed towards the liver and transmission stages are in their infancy but are receiving increasing attention as targeting these stages could be instrumental in eradicating malaria.
Sujet(s)
Antipaludiques/pharmacologie , Découverte de médicament , Foie/effets des médicaments et des substances chimiques , Paludisme/traitement médicamenteux , Animaux , Antipaludiques/synthèse chimique , Antipaludiques/composition chimique , Antipaludiques/usage thérapeutique , Humains , Foie/parasitologie , Transplantation hépatique , Structure moléculaireRÉSUMÉ
We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.
Sujet(s)
Protéines et peptides de signalisation intracellulaire/antagonistes et inhibiteurs , Protein-tyrosine kinases/antagonistes et inhibiteurs , Pyrazines/synthèse chimique , Pyrroles/synthèse chimique , Animaux , Lymphocytes B/effets des médicaments et des substances chimiques , Lymphocytes B/enzymologie , Protéines du sang/métabolisme , Cristallographie aux rayons X , Humains , Souris , Microsomes du foie/métabolisme , Modèles moléculaires , Structure moléculaire , Liaison aux protéines , Pyrazines/pharmacologie , Pyrazines/toxicité , Pyrroles/pharmacologie , Pyrroles/toxicité , Relation structure-activité , Syk kinaseRÉSUMÉ
A novel approach to design selective spleen tyrosine kinase (Syk) inhibitors is described. Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of autoimmune diseases such as asthma, rheumatoid arthritis, and SLE. Fostamatinib, a Syk inhibitor that successfully completed phase II clinical trials, also exhibits some undesirable side effects. More selective Syk inhibitors could offer safer, alternative treatments. Through a systematic evaluation of the kinome, we identified Pro455 and Asn457 in the Syk ATP binding site as a rare combination among sequence aligned kinases and hypothesized that optimizing the interaction between them and a Syk inhibitor molecule would impart high selectivity for Syk over other kinases. We report the structure-guided identification of three series of selective spleen tyrosine kinase inhibitors that support our hypothesis and offer useful guidance to other researchers in the field.
Sujet(s)
Inhibiteurs de protéines kinases/pharmacologie , Protein-tyrosine kinases/antagonistes et inhibiteurs , Rate/enzymologie , Conception de médicament , Humains , Modèles moléculaires , Inhibiteurs de protéines kinases/composition chimiqueRÉSUMÉ
Activation of p53 tumor suppressor by antagonizing its negative regulator murine double minute (MDM)2 has been considered an attractive strategy for cancer therapy and several classes of p53-MDM2 binding inhibitors have been developed. However, these compounds do not inhibit the p53-MDMX interaction, and their effectiveness can be compromised in tumors overexpressing MDMX. Here, we identify small molecules that potently block p53 binding with both MDM2 and MDMX by inhibitor-driven homo- and/or heterodimerization of MDM2 and MDMX proteins. Structural studies revealed that the inhibitors bind into and occlude the p53 pockets of MDM2 and MDMX by inducing the formation of dimeric protein complexes kept together by a dimeric small-molecule core. This mode of action effectively stabilized p53 and activated p53 signaling in cancer cells, leading to cell cycle arrest and apoptosis. Dual MDM2/MDMX antagonists restored p53 apoptotic activity in the presence of high levels of MDMX and may offer a more effective therapeutic modality for MDMX-overexpressing cancers.
Sujet(s)
Apoptose/physiologie , Hydantoïnes/pharmacologie , Modèles moléculaires , Protéines nucléaires/antagonistes et inhibiteurs , Protéines proto-oncogènes c-mdm2/antagonistes et inhibiteurs , Protéines proto-oncogènes/antagonistes et inhibiteurs , Protéine p53 suppresseur de tumeur/métabolisme , Apoptose/effets des médicaments et des substances chimiques , Technique de Western , Protéines du cycle cellulaire , Lignée cellulaire tumorale , Cristallisation , Dimérisation , Transfert d'énergie par résonance de fluorescence , Humains , Résonance magnétique nucléaire biomoléculaire , Protéines nucléaires/composition chimique , Protéines proto-oncogènes/composition chimique , Protéines proto-oncogènes c-mdm2/composition chimique , Transduction du signal/effets des médicaments et des substances chimiques , Transduction du signal/physiologie , Sels de tétrazolium , ThiazolesRÉSUMÉ
Recent success stories concerning the targeting of protein-protein interactions (PPIs) have led to an increased focus on this challenging target class for drug discovery. This article explores various avenues to assess the druggability of PPIs and describes a druggability decision flow chart, which can be applied to any PPI target. This flow chart not only covers small molecules but also peptidomimetics, peptides and conformationally restricted peptides as potential modalities for targeting PPIs. Additionally, a retrospective analysis of PPI druggability using various computational tools is summarized. The application of a systematic approach as presented in this paper will increase confidence that modulators (e.g., small organic molecules or peptides) can ultimately be identified for a particular target before a decision is made to commit significant discovery resources.
Sujet(s)
Protéines/composition chimique , Mimétisme moléculaire , Peptides/composition chimique , Préparations pharmaceutiques/composition chimique , Liaison aux protéinesRÉSUMÉ
Replacement of a secondary amide with a piperidine or azetidine moiety in a series of CCR5 antagonists led to the discovery of compounds with increased intrinsic permeability. This effort led to the identification of a potent CCR5 antagonist which exhibited an improved in vivo pharmacokinetic profile.
Sujet(s)
Amides/composition chimique , Composés aza/pharmacologie , Antagonistes des récepteurs CCR5 , Composés aza/composition chimique , Composés aza/pharmacocinétique , Relation structure-activitéRÉSUMÉ
This review will focus on the discovery and clinical development of small molecule antagonists of CCR5 for the treatment of HIV-1/AIDS, as well as for the potential treatment of inflammatory diseases. In particular, we will focus on the specific medicinal chemistry problems that were faced during the discovery of the molecules. We will also describe limited data from clinical development phases focusing on specific issues that arose during the clinical trials. Finally, we will touch on the mechanism of action of CCR5 antagonists.
Sujet(s)
Anti-inflammatoires non stéroïdiens/pharmacologie , Antagonistes des récepteurs CCR5 , Syndrome d'immunodéficience acquise/traitement médicamenteux , Animaux , Anti-inflammatoires non stéroïdiens/composition chimique , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/effets des médicaments et des substances chimiques , Humains , Masse moléculaireRÉSUMÉ
Starting with a high-throughput screening lead, a novel series of CCR5 antagonists was developed utilizing an information-based approach. Improvement of pharmacokinetic properties for the series was pursued by SAR exploration of the lead template. The synthesis, SAR and biological profiles of the series are described.
Sujet(s)
Agents antiVIH/composition chimique , Benzamides/composition chimique , Antagonistes des récepteurs CCR5 , Inhibiteurs de fusion du VIH/composition chimique , Pyrroles/composition chimique , Animaux , Agents antiVIH/synthèse chimique , Agents antiVIH/pharmacocinétique , Benzamides/synthèse chimique , Benzamides/pharmacologie , Inhibiteurs de fusion du VIH/synthèse chimique , Inhibiteurs de fusion du VIH/pharmacocinétique , Humains , Microsomes du foie/métabolisme , Pyrroles/synthèse chimique , Pyrroles/pharmacocinétique , Rats , Récepteurs CCR5/métabolisme , Relation structure-activitéRÉSUMÉ
The bicyclic 5-amino-3-azabicyclo[3.3.0]octanes were shown to be effective replacements for the 3-amino-8-azabicyclo[3.2.1]octane found in the CCR5 antagonist maraviroc.
Sujet(s)
Agents antiVIH/composition chimique , Composés azabicycliques/composition chimique , Antagonistes des récepteurs CCR5 , Cyclohexanes/composition chimique , Inhibiteurs de fusion du VIH/composition chimique , Triazoles/composition chimique , Agents antiVIH/synthèse chimique , Agents antiVIH/pharmacologie , Lignée cellulaire tumorale , Cyclohexanes/synthèse chimique , Cyclohexanes/pharmacologie , Inhibiteurs de fusion du VIH/synthèse chimique , Inhibiteurs de fusion du VIH/pharmacologie , Humains , Maraviroc , Modèles chimiques , Récepteurs CCR5/métabolisme , Triazoles/synthèse chimique , Triazoles/pharmacologieRÉSUMÉ
The bicyclic 5-amino-3-azabicyclo[3.3.0]octanes were shown to be effective replacements for the conformationally restricted 4-aminopiperidine ring found in several series of CCR5 antagonists.
Sujet(s)
Antagonistes des récepteurs CCR5 , Évaluation préclinique de médicament , Pipéridines/composition chimique , Modèles moléculairesRÉSUMÉ
Replacement of a secondary amide with an N-acyl or N-sulfonyl gem-disubstituted azacyle in a series of CCR5 antagonists led to the identification of compounds with excellent in vitro HIV antiviral activity and increased intrinsic membrane permeability.
Sujet(s)
Amides/composition chimique , Agents antiVIH/composition chimique , Composés aza/composition chimique , Antagonistes des récepteurs CCR5 , Inhibiteurs de fusion du VIH/composition chimique , Agents antiVIH/synthèse chimique , Agents antiVIH/pharmacologie , Composés aza/synthèse chimique , Composés aza/pharmacologie , Lignée cellulaire tumorale , Perméabilité des membranes cellulaires/effets des médicaments et des substances chimiques , Inhibiteurs de fusion du VIH/synthèse chimique , Inhibiteurs de fusion du VIH/pharmacologie , Humains , Récepteurs CCR5/métabolismeRÉSUMÉ
The lipoglycodepsipeptide antibiotic ramoplanin is proposed to inhibit bacterial cell wall biosynthesis by binding to intermediates along the pathway to mature peptidoglycan, which interferes with further enzymatic processing. Two sequential enzymatic steps can be blocked by ramoplanin, but there is no definitive information about whether one step is inhibited preferentially. Here we use inhibition kinetics and binding assays to assess whether ramoplanin and the related compound enduracidin have an intrinsic preference for one step over the other. Both ramoplanin and enduracidin preferentially inhibit the transglycosylation step of peptidoglycan biosynthesis compared with the MurG step. The basis for stronger inhibition is a greater affinity for the transglycosylase substrate Lipid II over the MurG substrate Lipid I. These results provide compelling evidence that ramoplanin's and enduracidin's primary cellular target is the transglycosylation step of peptidoglycan biosynthesis.
Sujet(s)
Antibactériens/composition chimique , Antibactériens/pharmacologie , Depsipeptides/composition chimique , Depsipeptides/pharmacologie , Glycopeptides/composition chimique , Peptides cycliques/composition chimique , Peptides cycliques/pharmacologie , Antibactériens/synthèse chimique , Depsipeptides/synthèse chimique , Escherichia coli/effets des médicaments et des substances chimiques , Cinétique , Tests de sensibilité microbienne , Modèles moléculaires , Peptides cycliques/synthèse chimiqueRÉSUMÉ
A general method for the deglycosidation of glycopeptide antibiotics has been developed. Treatment of vancomycin, ristocetin, and ramoplanin with anhydrous HF results in efficient cleavage of the sugars to provide the corresponding aglycons in high yield.
Sujet(s)
Antibactériens/composition chimique , Depsipeptides , Peptides cycliques/composition chimique , Ristocétine/composition chimique , Vancomycine/composition chimique , Chromatographie en phase liquide à haute performance , Acide fluorhydrique , Indicateurs et réactifs , Pyridines/composition chimique , SolvantsRÉSUMÉ
Full details of a convergent total synthesis of the ramoplanin A2 and ramoplanose aglycon are disclosed. Three key subunits composed of residues 3-9 (heptapeptide 15), pentadepsipeptide 26 (residues 1, 2 and 15-17), and pentapeptide 34 (residues 10-14) were prepared, sequentially coupled, and cyclized to provide the 49-membered depsipeptide core of the aglycon. Key to the preparation of the pentadepsipeptide 26 incorporating the backbone ester was the asymmetric synthesis of an orthogonally protected l-threo-beta-hydroxyasparagine and the development of effective and near-racemization free conditions for esterification of its hindered alcohol (EDCI, DMAP, 0 degrees C). The coupling sites were chosen to maximize the convergency of the synthesis including that of the three subunits, to prevent late stage racemization of carboxylate-activated phenylglycine-derived residues, and to enlist beta-sheet preorganization of an acyclic macrocyclization substrate for 49-membered ring closure. By altering the order of final couplings, two macrocyclization sites, Phe(9)-d-Orn(10) and Gly(14)-Leu(15), were examined. Macrocyclization at the highly successful Phe(9)-d-Orn(10) site (89%) may benefit from both beta-sheet preorganization as well as closure at a d-amine terminus within the confines of a beta-turn at the end of the H-bonded antiparallel beta-strands. A more modest, but acceptable macrocyclization reaction at the Gly(14)-Leu(15) site (40-50%) found at the other end of the H-bonded antiparallel beta-strands within a small flexible loop may also benefit from preorganization of the cyclization substrate, is conducted on a substrate incapable of competitive racemization, and accommodates the convergent preparation of analogues bearing depsipeptide modifications. Deliberate late-stage incorporation of the subunit bearing the labile depsipeptide ester and a final stage Asn(1) side-chain introduction provides future access to analogues of the aglycons which themselves are equally potent or more potent than the natural products in antimicrobial assays.
Sujet(s)
Antibactériens/synthèse chimique , Depsipeptides , Glycoprotéines/synthèse chimique , Peptides cycliques/synthèse chimique , Antibactériens/composition chimique , Glycoprotéines/composition chimique , Modèles moléculaires , Oligopeptides/synthèse chimique , Oligopeptides/composition chimique , Peptides cycliques/composition chimique , Structure secondaire des protéinesRÉSUMÉ
A convergent total synthesis of the ramoplanin A2 and ramoplanose aglycon is disclosed. Three key subunits composed of residues 3-9 (heptapeptide 15), pentadepsipeptide 26, and pentapeptide 34 (residues 10-14) were prepared, sequentially coupled, and cyclized to provide the 49-membered depsipeptide core of the aglycon. Key to the preparation of the pentadepsipeptide 26 incorporating the backbone ester was the asymmetric synthesis of an orthogonally protected L-threo-beta-hydroxyasparagine and the development of effective and near-racemization free conditions for esterification of its hindered alcohol (EDCI, DMAP, 0 degrees C). The coupling sites were chosen to maximize the convergency of the synthesis including that of the three subunits, to prevent late stage racemization of carboxylate-activated phenylglycine-derived residues, and to enlist beta-sheet preorganization of an acyclic macrocyclization substrate for 49-membered ring closure. As such, macrocyclization at the chosen Phe(9)-D-Orn(10) site may benefit from both beta-sheet preorganization as well as closure at a D-amine terminus. Deliberate late stage incorporation of the subunit bearing the labile depsipeptide ester and a final stage Asn(1) side chain introduction provides future access to analogues of the aglycons which themselves are reported to be equally potent or more potent than the natural products in antimicrobial assays.