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The rapidly expanding demand for photovoltaics (PVs) requires stable, quick, and easy to manufacture solar cells based on socioeconomically and ecologically viable earth-abundant resources. Sb2S3 has been a potential candidate for solar PVs and the efficiency of planar Sb2S3 thin-film solar cells has witnessed a reasonable rise from 5.77% in 2014 to 8% in 2022. Herein, the aim is to bring new insight into Sb2S3 solar cell research by investigating how the bulk and surface properties of the Sb2S3 absorber and the current-voltage and deep-level defect characteristics of solar cells based on these films are affected by the ultrasonic spray pyrolysis deposition temperature and the molar ratio of thiourea to SbEX in solution. The properties of the Sb2S3 absorber are characterized by bulk- and surface-sensitive methods. Solar cells are characterized by temperature-dependent current-voltage, external quantum efficiency, and deep-level transient spectroscopy measurements. In this paper, the first thin-film solar cells based on a planar Sb2S3 absorber grown from antimony ethyl xanthate (SbEX) by ultrasonic spray pyrolysis in air are demonstrated. Devices based on the Sb2S3 absorber grown at 200 °C, especially from a solution of thiourea and SbEX in a molar ratio of 4.5, perform the best by virtue of suppressed surface oxidation of Sb2S3, favorable band alignment, Sb-vacancy concentration, a continuous film morphology, and a suitable film thickness of 75 nm, achieving up to 4.1% power conversion efficiency, which is the best efficiency to date for planar Sb2S3 solar cells grown from xanthate-based precursors. Our findings highlight the importance of developing synthesis conditions to achieve the best solar cell device performance for an Sb2S3 absorber layer pertaining to the chosen deposition method, experimental setup, and precursors.
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The identification of novel inhaled p38α/ß mitogen-activated protein kinases (MAPK) (MAPK14/11) inhibitors suitable for the treatment of pulmonary inflammatory conditions has been described. A rational drug design approach started from the identification of a novel tetrahydronaphthalene series, characterized by nanomolar inhibition of p38α with selectivity over p38γ and p38δ isoforms. SAR optimization of 1c is outlined, where improvements in potency against p38α and ligand-enzyme dissociation kinetics led to several compounds showing pronounced anti-inflammatory effects in vitro (inhibition of TNFα release). Targeting of the defined physicochemical properties allowed the identification of compounds 3h, 4e, and 4f, which showed, upon intratracheal instillation, low plasma levels, prolonged lung retention, and anti-inflammatory effects in a rat acute model of a bacterial endotoxin-induced pulmonary inflammation. Compound 4e, in particular, displayed remarkable efficacy and duration of action and was selected for progression in disease models of asthma and chronic obstructive pulmonary disease (COPD).
Assuntos
Proteína Quinase 14 Ativada por Mitógeno , Pneumonia , Inibidores de Proteínas Quinases , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Desenho de Fármacos , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Fosforilação , Pneumonia/tratamento farmacológico , Pneumonia/enzimologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Ratos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
Human DNA polymerase theta (Polθ), which is essential for microhomology-mediated DNA double strand break repair, has been proposed as an attractive target for the treatment of BRCA deficient and other DNA repair pathway defective cancers. As previously reported, we recently identified the first selective small molecule Polθ in vitro probe, 22 (ART558), which recapitulates the phenotype of Polθ loss, and in vivo probe, 43 (ART812), which is efficacious in a model of PARP inhibitor resistant TNBC in vivo. Here we describe the discovery, biochemical and biophysical characterization of these probes including small molecule ligand co-crystal structures with Polθ. The crystallographic data provides a basis for understanding the unique mechanism of inhibition of these compounds which is dependent on stabilization of a "closed" enzyme conformation. Additionally, the structural biology platform provided a basis for rational optimization based primarily on reduced ligand conformational flexibility.
Assuntos
Reparo do DNA por Junção de Extremidades , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Ligantes , DNA/metabolismo , DNA Polimerase tetaRESUMO
To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining, without targeting Non-Homologous End Joining. In addition, ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a PARP inhibitor. Genetic perturbation screening revealed that defects in the 53BP1/Shieldin complex, which cause PARP inhibitor resistance, result in in vitro and in vivo sensitivity to small molecule Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells whilst the inhibition of DNA nucleases that promote end-resection reversed these effects, implicating these in the synthetic lethal mechanism-of-action. Taken together, these observations describe a drug class that elicits BRCA-gene synthetic lethality and PARP inhibitor synergy, as well as targeting a biomarker-defined mechanism of PARPi-resistance.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Reparo do DNA/efeitos dos fármacos , DNA Polimerase Dirigida por DNA/genética , Inibidores da Síntese de Ácido Nucleico/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Mutações Sintéticas Letais/efeitos dos fármacos , Regulação Alostérica , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , DNA Polimerase Dirigida por DNA/metabolismo , Desoxirribonucleases/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Recombinação Homóloga/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Organoides/efeitos dos fármacos , Neoplasias Ovarianas/genética , Ratos , Mutações Sintéticas Letais/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/deficiência , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , DNA Polimerase tetaRESUMO
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.
Assuntos
Antineoplásicos/síntese química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Isoxazóis/síntese química , Resorcinóis/síntese química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Ligação Competitiva , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Polarização de Fluorescência , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Isoxazóis/farmacocinética , Isoxazóis/farmacologia , Camundongos , Camundongos Nus , Modelos Moleculares , Transplante de Neoplasias , Resorcinóis/farmacocinética , Resorcinóis/farmacologia , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
Atropisomeric drug substances are known to have different biological properties. Compounds containing the N-benzoylbenzazepine motif have been shown to exhibit energetically restricted rotation around the Ar(CO)N axis. Herein we report, for the first time, the synthesis, physical characterisation and anti-viral profiles of a series of C-4 and C-5 methylated thieno-benzazepines. NMR analysis reveals that incorporation of a single additional substituent at either of these loci influences the conformational dynamics of the azepine ring system. In the case of the C-5 alkyl analogues, the influence of the new stereocentre is so pronounced that its absolute configuration determines which unique atropisomer is obtained following the generation of the benzazepine nucleus. Screening of the alkylated derivatives for their anti-respiratory syncytial virus (RSV) activity indicates that the desired viral pathogenicity is strongly associated with the conformation adopted by the modified tricyclic scaffolds. This is particularly evident in the case of the C-5 homologues in which one atropisomer was found to be potently active and the other essentially inert. These results provide compelling evidence that we have determined the bioactive conformation shared by RSV inhibitors that employ the thienobenazapine nucleus as their core molecular architecture. Furthermore, the understanding obtained from these studies may make it possible to design improved agents against RSV infection in the future.
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[This corrects the article DOI: 10.1039/C8MD00033F.].
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Structure-based drug design strategies based on X-ray crystallographic data of ligands bound to biological targets or computationally derived pharmacophore models have been introduced over the past 25 years or so. These have now matured and are deeply embedded in the drug discovery process in most pharmaceutical and biotechnology companies where they continue to play a major part in the discovery of new medicines and drug candidates. Newly developed NMR methods can now provide a full description of the conformations in which ligands exist in free solution, crucially allowing those that are dominant to be identified. Integrating experimentally determined conformational information on active and inactive molecules in drug discovery programmes, alongside the existing techniques, should have a major impact on the success of drug discovery.
Assuntos
Química Farmacêutica/métodos , Desenho de Fármacos , Descoberta de Drogas/métodos , Biotecnologia/métodos , Biotecnologia/tendências , Química Farmacêutica/tendências , Cristalografia por Raios X/métodos , Descoberta de Drogas/tendências , Indústria Farmacêutica/métodos , Indústria Farmacêutica/tendências , Humanos , Ligantes , Espectroscopia de Ressonância Magnética/métodos , Relação Estrutura-AtividadeRESUMO
We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (K(d) = 1.7 nmol/L) and proliferation of human tumor cells with GI(50) values of approximately 2 to 40 nmol/L, inducing G(1)-G(2) arrest and apoptosis. Activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. NVP-AUY922 was glucuronidated less than previously described isoxazoles, yielding higher drug levels in human cancer cells and xenografts. Daily dosing of NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI(50). This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. Therapeutic effects were concordant with changes in pharmacodynamic markers, including induction of HSP72 and depletion of ERBB2, CRAF, cyclin-dependent kinase 4, phospho-AKT/total AKT, and hypoxia-inducible factor-1alpha, determined by Western blot, electrochemiluminescent immunoassay, or immunohistochemistry. NVP-AUY922 also significantly inhibited tumor cell chemotaxis/invasion in vitro, WM266.4 melanoma lung metastases, and lymphatic metastases from orthotopically implanted PC3LN3 prostate carcinoma. NVP-AUY922 inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts. Collectively, the data show that NVP-AUY922 is a potent, novel inhibitor of HSP90, acting via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. NVP-AUY922 has entered phase I clinical trials.
Assuntos
Divisão Celular/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Isoxazóis/uso terapêutico , Metástase Neoplásica/prevenção & controle , Neovascularização Patológica/prevenção & controle , Resorcinóis/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Carcinoma/metabolismo , Ciclo Celular/efeitos dos fármacos , Feminino , Humanos , Isoxazóis/farmacocinética , Camundongos , Camundongos Nus , Resorcinóis/farmacocinética , Transplante HeterólogoRESUMO
Virtual screening against a pCDK2/cyclin A crystal structure led to the identification of a potent and novel CDK2 inhibitor, which exhibited an unusual mode of interaction with the kinase binding motif. With the aid of X-ray crystallography and modelling, a medicinal chemistry strategy was implemented to probe the interactions seen in the crystal structure and to establish SAR. A fragment-based approach was also considered but a different, more conventional, binding mode was observed. Compound selectivity against GSK-3beta was improved using a rational design strategy, with crystallographic verification of the CDK2 binding mode.
Assuntos
Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Inibidores de Proteínas Quinases/químicaRESUMO
We have designed four generations of a low molecular weight fragment library for use in NMR-based screening against protein targets. The library initially contained 723 fragments which were selected manually from the Available Chemicals Directory. A series of in silico filters and property calculations were developed to automate the selection process, allowing a larger database of 1.79 M available compounds to be searched for a further 357 compounds that were added to the library. A kinase binding pharmacophore was then derived to select 174 kinase-focused fragments. Finally, an additional 61 fragments were selected to increase the number of different pharmacophores represented within the library. All of the fragments added to the library passed quality checks to ensure they were suitable for the screening protocol, with appropriate solubility, purity, chemical stability, and unambiguous NMR spectrum. The successive generations of libraries have been characterized through analysis of structural properties (molecular weight, lipophilicity, polar surface area, number of rotatable bonds, and hydrogen-bonding potential) and by analyzing their pharmacophoric complexity. These calculations have been used to compare the fragment libraries with a drug-like reference set of compounds and a set of molecules that bind to protein active sites. In addition, an analysis of the overall results of screening the library against the ATP binding site of two protein targets (HSP90 and CDK2) reveals different patterns of fragment binding, demonstrating that the approach can find selective compounds that discriminate between related binding sites.