ABSTRACT
The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling1 and is altered in over 20% of cancers2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.
Subject(s)
Adenosine Triphosphatases , DNA Helicases , Nuclear Proteins , Prostatic Neoplasms , Transcription Factors , Adenosine Triphosphatases/metabolism , Animals , Benzamides , DNA Helicases/genetics , Enhancer Elements, Genetic , Genes, myc , Hepatocyte Nuclear Factor 3-alpha , Humans , Male , Nitriles , Nuclear Proteins/genetics , Oncogenes , Phenylthiohydantoin , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Receptors, Androgen , Transcription Factors/genetics , Transcriptional Regulator ERG , Xenograft Model Antitumor AssaysABSTRACT
Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the ß2-adrenergic receptor, including extracellular loops, were developed and used to guide the design.
Subject(s)
Drug Design , Quinazolines/chemical synthesis , Receptors, Pituitary Hormone/antagonists & inhibitors , Humans , Molecular Structure , Quinazolines/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
Melanin concentrating hormone receptor 1 (MCHR1) antagonists have potential for the treatment of obesity and several CNS disorders. In the preceding article, we have described a novel series of quinazolines as MCHR1 antagonists and demonstrated in vivo proof of principle with an early lead. Herein we describe the detailed SAR and SPR studies to identify an optimized lead candidate having good efficacy in a sub-chronic DIO model with a good cardiovascular safety window.
Subject(s)
Drug Design , Quinazolines/chemical synthesis , Receptors, Pituitary Hormone/antagonists & inhibitors , Cardiovascular Diseases/prevention & control , Humans , Quinazolines/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays role in several disorders such as obesity, stress, depression and anxiety. The synthesis and biological evaluation of novel benzimidazole derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified.
Subject(s)
Anti-Obesity Agents/chemistry , Anti-Obesity Agents/therapeutic use , Benzimidazoles/chemistry , Benzimidazoles/therapeutic use , Obesity/drug therapy , Receptors, Somatostatin/antagonists & inhibitors , Receptors, Somatostatin/metabolism , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Humans , Mice , Mice, Inbred C57BL , Models, Molecular , Protein Binding , Weight Loss/drug effectsABSTRACT
Low-barrier molecular rotary motors having rotaxane architecture can be constructed using a cucurbituril host and a polyyne guest serving as stator and rotator, respectively. The repulsive interaction between these components is supported by molecular mechanics calculations with model systems and experimentally verified by X-ray crystallography with several synthetic host-guest complexes, all suggesting that the diyne rod floats at the center of the macrocyclic host with no apparent van der Waals contacts between them. Further support for these interactions is suggested by microcalorimetry measurements.
Subject(s)
Rotaxanes/chemical synthesis , Bridged-Ring Compounds/chemistry , Calorimetry , Crystallography, X-Ray , Imidazoles/chemistry , Polyynes/chemistry , Rotaxanes/chemistry , Thermodynamics , TitrimetryABSTRACT
A practical method for the separation and purification of cucurbituril (CB) hexamers was developed on the basis of affinity chromatography using aminopentylaminomethylated polystyrene beads. This recyclable resin, which can be used repeatedly, facilitates the general preparation of cucurbituril derivatives and compensates for the usually moderate yields and mixed products that characterize the acid-catalyzed synthesis of CB derivatives. This technique allows convenient, rapid isolation of rare substituted cucurbiturils, including hexacyclohexanocucurbit[6]uril and dodecamethylcucurbit[6]uril. [reaction: see text]
Subject(s)
Bridged-Ring Compounds/isolation & purification , Chromatography, Affinity/methods , Imidazoles/isolation & purification , Catalysis , Indicators and Reagents , Methylation , Models, Molecular , Polystyrenes/chemistryABSTRACT
We describe the synthesis and characterization of 3-alkoxy-pyrrolo[1,2-b]pyrazolines as novel selective androgen receptor (AR) modulators that possess excellent physicochemical properties for transdermal administration. Compound 26 bound to human AR with an IC50 of 0.7 nM with great selectivity over other nuclear hormone receptors and potently activated AR in a C2C12 muscle cell reporter gene assay with an EC50 of 0.5 nM. It showed high aqueous solubility of 1.3 g/L at pH 7.4, and an in silico model as well as a customized parallel artificial membrane permeability assay indicated good skin permeation. Indeed, when measuring skin permeation through excised human skin, an excellent flux of 2 µg/(cm(2)·h) was determined without any permeation enhancers. In a 2 week Hershberger model using castrated rats, the compound showed dose-dependent effects fully restoring skeletal muscle weight at 0.3 mg/kg/day after subcutaneous administration with high selectivity over prostate stimulation.
Subject(s)
Androgen Receptor Antagonists/chemistry , Androgens/chemistry , Azabicyclo Compounds/chemistry , Pyrazoles/chemistry , Receptors, Androgen/chemistry , Administration, Cutaneous , Androgen Receptor Antagonists/metabolism , Androgen Receptor Antagonists/pharmacokinetics , Androgens/metabolism , Animals , Area Under Curve , Azabicyclo Compounds/metabolism , Azabicyclo Compounds/pharmacokinetics , Binding Sites , Binding, Competitive , Cell Line , Chemical Phenomena , Crystallography, X-Ray , Humans , Male , Metabolic Clearance Rate , Mice , Models, Chemical , Models, Molecular , Molecular Structure , Protein Structure, Tertiary , Pyrazoles/metabolism , Pyrazoles/pharmacokinetics , Rats, Wistar , Receptors, Androgen/metabolism , Skin/metabolismABSTRACT
Aldol products (3-hydroxy acids) with an allyl-protected hydroxy group were converted to amino alcohols by Curtius rearrangement. Combination of the carboxylic acid with the amino alcohols gave the amides 10. Ring-closing metathesis led to the 12-membered lactams 12 as mixtures of E/Z-isomers. The scheme was also transferred to the solid-phase. In this case the macrolactams are formed via cyclorelease. For a pair of E/Z-isomers the solution conformation was determined by ROESY spectroscopy.