RESUMO
Advanced basal cell carcinomas (BCCs) circumvent Smoothened (SMO) inhibition by activating GLI transcription factors to sustain the high levels of Hedgehog (HH) signaling required for their survival. Unfortunately, there is a lack of efficacious therapies. We performed a gene expression-based drug repositioning screen in silico and identified the FDA-approved histone deacetylase (HDAC) inhibitor, vorinostat, as a top therapeutic candidate. We show that vorinostat only inhibits proliferation of BCC cells in vitro and BCC allografts in vivo at high dose, limiting its usefulness as a monotherapy. We leveraged this in silico approach to identify drug combinations that increase the therapeutic window of vorinostat and identified atypical PKC Æ/Ê (aPKC) as a HDAC costimulator of HH signaling. We found that aPKC promotes GLI1-HDAC1 association in vitro, linking two positive feedback loops. Combination targeting of HDAC1 and aPKC robustly inhibited GLI1, lowering drug doses needed in vitro, in vivo, and ex vivo in patient-derived BCC explants. We identified a bioavailable and selective small-molecule aPKC inhibitor, bringing the pharmacological blockade of aPKC and HDAC1 into the realm of clinical possibility. Our findings provide a compelling rationale and candidate drugs for combined targeting of HDAC1 and aPKC in HH-dependent cancers.
Assuntos
Carcinoma Basocelular/tratamento farmacológico , Histona Desacetilase 1/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Isoenzimas/efeitos dos fármacos , Proteína Quinase C/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Aloenxertos , Animais , Carcinoma Basocelular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Biologia Computacional , Combinação de Medicamentos , Descoberta de Drogas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ouriços/genética , Ouriços/metabolismo , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/química , Isoenzimas/metabolismo , Camundongos , Camundongos Knockout , Proteína Quinase C/metabolismo , Transdução de Sinais , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/genética , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismoRESUMO
The spread of intra-abdominal cancers is a vexing clinical problem for which there is no widely effective treatment. We discovered previously that (2E)-3-[(4-tert-butylphenyl)sulfonyl]acrylonitrile (1) induced cancer cell apoptosis during adhesion to normal mesothelial cells which line the peritoneum. We recently demonstrated that the sulfonylacrylonitrile portion of 1 and hydrophobic aryl substitution were essential for pro-apoptotic activity in cancer cells. Here we synthesized a diverse series of analogues of 1 in order to improve the efficacy and pharmaceutical properties. Analogues and 1 were compared in their ability to cause cancer cell death during adhesion to normal mesothelial cell monolayers. Potent analogues identified in the in vitro assay were validated and found to exhibit improved inhibition of intra-abdominal cancer in two clinically relevant murine models of ovarian and pancreatic cancer spread and metastasis, highlighting their potential clinical use as an adjunct to surgical resection of cancers.
Assuntos
Acrilonitrila/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Sulfonas/farmacologia , Acrilonitrila/síntese química , Acrilonitrila/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Células HT29 , Humanos , Camundongos , Estrutura Molecular , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/secundário , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/secundário , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/químicaRESUMO
The vast majority of cancer patients die from metastasis, the process by which cancer cells spread to secondary tissues through body fluids. Peritoneal carcinomatosis is a type of metastasis in which cancer cells gain access to the intra-abdominal cavity and then implant in the peritoneum, the thin tissue that lines the abdominal wall and internal organs. Unfortunately, peritoneal carcinomatosis can occur following surgical resection of intra-abdominal malignancies. We previously reported proapoptotic activity of (2E)-3-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2-propenenitrile (BAY 11-7085, 1) on colon and pancreatic cancer cells during adhesion and demonstrated that this compound could significantly inhibit peritoneal carcinomatosis in mice.(1,2) In order to determine the chemical basis of the anti-metastatic properties of BAY 11-7085, a series of analogs were synthesized and evaluated for their ability to induce apoptosis in pancreatic and ovarian cancer cells during adhesion to mesothelial cells, which line the surface of the peritoneum. The co-culture assay results were validated using a murine peritoneal carcinomatosis model. These analogs may greatly benefit patients undergoing surgical resections of colorectal, pancreatic, and ovarian cancers depending on their tolerability.
Assuntos
Acrilonitrila/química , Acrilonitrila/uso terapêutico , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Acrilonitrila/síntese química , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Carcinoma/patologia , Carcinoma/secundário , Linhagem Celular Tumoral , Técnicas de Cocultura , Feminino , Humanos , Camundongos , Nitrilas/síntese química , Nitrilas/química , Nitrilas/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Ovário/efeitos dos fármacos , Ovário/patologia , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/secundário , Peritônio/efeitos dos fármacos , Peritônio/patologia , Sulfonas/síntese química , Sulfonas/química , Sulfonas/uso terapêuticoRESUMO
Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (32) with antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized.
Assuntos
Compostos de Anilina/síntese química , Antineoplásicos/síntese química , Pirróis/síntese química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Triazinas/síntese química , Administração Oral , Quinase do Linfoma Anaplásico , Compostos de Anilina/farmacocinética , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Técnicas In Vitro , Camundongos , Camundongos SCID , Microssomos Hepáticos/metabolismo , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Triazinas/farmacocinética , Triazinas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The elaboration of a novel scaffold for the inhibition of JAK2 and FAK kinases was targeted in order to provide a dual inhibitor that could target divergent pathways for tumor cell progression.
Assuntos
Proteína-Tirosina Quinases de Adesão Focal/química , Janus Quinase 2/química , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Progressão da Doença , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Mutação , Neoplasias/genética , Neoplasias/patologia , Inibidores de Proteínas Quinases/síntese química , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Fatores de TempoRESUMO
The incorporation of R,R-1,2-diaminocyclohexane at C4 in a series of 2,4-diaminopyrimidines led to a number of ALK inhibitors in which optimized activity was achieved by conversion of the 2-amino group into a methanesulfonamide. Tumor growth inhibition was observed when an orally bioavailable analog was evaluated in a Karpas-299 tumor xenograft mouse model.
Assuntos
Antineoplásicos/síntese química , Cicloexilaminas/síntese química , Pirimidinas/síntese química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Administração Oral , Quinase do Linfoma Anaplásico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Cicloexilaminas/administração & dosagem , Cicloexilaminas/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Bombas de Infusão , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The HGF-c-Met signaling axis is an important paracrine mediator of epithelial-mesenchymal cell interactions involving the regulation of multiple cellular activities including cell motility, mitogenesis, morphogenesis, and angiogenesis. Dysregulation of c-Met signaling (e.g., overexpression or increased activation) is associated with the development of a wide range of tumor types; thus, inhibiting the HGF-c-Met pathway is predicted to lead to anti-tumor effects in many cancers. Elaboration of a 2-arylaminopyrimidine scaffold led to a series of potent c-Met inhibitors bearing a C4-2-amino-N-methylbenzamide group. Specifically, a series of C2-benzazepinone analogs demonstrated potent inhibition of c-Met in enzymatic and cellular assays. Kinase selectivity could be tuned by varying the nature of the alkyl group on the benzazepinone nitrogen.
Assuntos
Compostos Bicíclicos com Pontes/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirimidinas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Humanos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Relação Estrutura-AtividadeRESUMO
Elaboration of the SAR around a series of 2,4-diaminopyrimidines led to a number of c-Met inhibitors in which kinase selectivity was modulated by substituents appended on the C4-aminobenzamide ring and the nature of the C2-aminoaryl ring. Further lead optimization of the C2-aminoaryl group led to benzoxazepine analogs whose pharmaceutical properties were modulated by the nature of the substituent on the benzoxazepine nitrogen. Tumor stasis (with partial regressions) were observed when an orally bioavailable analog was evaluated in a GTL-16 tumor xenograft mouse model. Subsequent PK/PD studies suggested that a metabolite contributed to the overall in vivo response.
Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirimidinas/química , Pirimidinas/uso terapêutico , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Humanos , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Dysregulation of the anaplastic lymphoma kinase (ALK) is implicated in a variety of cancers. A series of tetrahydropyrido[2,3-b]pyrazines was constructed as ring-constrained analogs of a known aminopyridine kinase scaffold. Chemistry was developed to rapidly elaborate the SAR, structural elements impacting ALK inhibitory activity were exploited, and kinase selective analogs were identified that inhibit ALK with IC(50) values approximately 10 nM (enzyme) and approximately 150 nM (cell).
Assuntos
Antineoplásicos/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazinas/química , Quinase do Linfoma Anaplásico , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Simulação por Computador , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/metabolismo , Pirazinas/síntese química , Pirazinas/farmacologia , Receptores Proteína Tirosina Quinases , Relação Estrutura-AtividadeRESUMO
A stereoselective halo-etherification of chiral enamides is described here. This work provides an approach to halogen containing cyclic ethers and reveals further mechanistic insights to the chemistry of chiral enamides.
Assuntos
Éteres Cíclicos/síntese química , Hidrocarbonetos Halogenados/síntese química , Modelos Moleculares , Estrutura MolecularRESUMO
Thiazolium azomethine ylides, equipped with a C-2 methanethiol group, participate in an efficient [3 + 2] cycloaddition reaction with acetylene derivatives to yield unique pyrrolo[2,1-b]thiazoles. The elimination of the methanethiol leaving group from the cycloadduct has replaced the need for a separate oxidation step and suppresses ring-opening side reactions. Products were obtained in short synthetic sequences to demonstrate their use as a scaffold for compound libraries.
Assuntos
Compostos Azo/química , Pirróis/síntese química , Tiazóis/química , Tiazóis/síntese química , Tiossemicarbazonas/química , Alcinos/química , Técnicas de Química Combinatória , Ciclização , Estrutura Molecular , Pirróis/químicaRESUMO
Total syntheses of indoloquinolizidine alkaloid (+/-)-, R-(+)-, and S-(-)-deplancheine are described here. The synthesis features an enantioselective intramolecular formal aza-[3 + 3] cycloaddition for the construction of the quinolizidine CD-ring. This application serves to introduce a new synthetic strategy for the synthesis of indoloquinolizidine alkaloids.
Assuntos
Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Espectroscopia de Ressonância Magnética , EstereoisomerismoRESUMO
[reaction: see text] A 19-step stereoselective total synthesis of (+/-)-tangutorine is described here. The total synthesis features an intramolecular aza-[3 + 3] formal cycloaddition strategy and also a Heck coupling for constructing the C2-C3 bond. This work provides a novel approach toward the indoloquinolizidine family of alkaloids.
Assuntos
Alcaloides/química , Compostos Aza/química , Carbolinas/química , Carbolinas/síntese química , Indolquinonas/química , Quinolizinas/química , Quinolizinas/síntese química , Estrutura Molecular , EstereoisomerismoRESUMO
A highly stereoselective preparation of novel chiral (E)-alpha-haloenamides under mild conditions utilizing magnesium halide salts is described. This unexpected mild and efficient hydrohalogenation reaction highlights another synthetic utility of ynamides. [reaction: see text]
RESUMO
A detailed account regarding a formal [3 + 3] cycloaddition method using 4-hydroxy-2-pyrones and 1,3-diketones is described here. This formal cycloaddition reaction or annulation reaction is synthetically useful for constructing 2H-pyranyl heterocycles. The usage of alpha,beta-unsaturated iminium salts is significant in controlling competing reaction pathways to give exclusively 2H-pyrans. Most significantly, experimental evidence is provided to support the mechanism of this reaction that involves a sequential Knoevenagel condensation and a reversible 6pi-electron electrocyclic ring-closure of 1-oxatrienes.
Assuntos
Química Orgânica/métodos , Cetonas/química , Piranos/síntese química , Pironas/química , Alcenos/química , Catálise , Cristalografia por Raios X , Ciclização , Iminas/química , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oxirredução , Sais/síntese química , EstereoisomerismoRESUMO
The first asymmetric Ficini-Claisen rearrangement using chiral ynamides is described. At relatively low temperatures, the Ficini-Claisen rearrangement can be efficiently promoted by p-nitrobenzenesulfonic acid leading to high diastereoselectivity for a range of different allylic alcohols and chiral ynamides. [reaction: see text]