RESUMO
PARP1 is a multifaceted component of DNA repair and chromatin remodeling, making it an effective therapeutic target for cancer therapy. The recently reported proteolytic targeting chimera (PROTAC) could effectively degrade PARP1 through the ubiquitin-proteasome pathway, expanding the therapeutic application of PARP1 blocking. In this study, a series of nitrogen heterocyclic PROTACs were designed and synthesized through ternary complex simulation analysis based on our previous work. Our efforts have resulted in a potent PARP1 degrader D6 (DC50 = 25.23 nM) with high selectivity due to nitrogen heterocyclic linker generating multiple interactions with the PARP1-CRBN PPI surface, specifically. Moreover, D6 exhibited strong cytotoxicity to triple negative breast cancer cell line MDA-MB-231 (IC50 = 1.04 µM). And the proteomic results showed that the antitumor mechanism of D6 was found that intensifies DNA damage by intercepting the CDC25C-CDK1 axis to halt cell cycle transition in triple-negative breast cancer cells. Furthermore, in vivo study, D6 showed a promising PK property with moderate oral absorption activity. And D6 could effectively inhibit tumor growth (TGI rate = 71.4 % at 40 mg/kg) without other signs of toxicity in MDA-MB-321 tumor-bearing mice. In summary, we have identified an original scaffold and potent PARP1 PROTAC that provided a novel intervention strategy for the treatment of triple-negative breast cancer.
Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Camundongos , Animais , Neoplasias de Mama Triplo Negativas/patologia , Proteômica , Proliferação de Células , Pontos de Checagem do Ciclo Celular , Nitrogênio , Linhagem Celular Tumoral , Fosfatases cdc25 , Poli(ADP-Ribose) Polimerase-1 , Proteína Quinase CDC2RESUMO
BRD9 is a pivotal epigenetic factor involved in cancers and inflammatory diseases. Still, the limited selectivity and poor phenotypic activity of targeted agents make it an atypically undruggable target. PROTAC offers an alternative strategy for overcoming the issue. In this study, we explored diverse E3 ligase ligands for the contribution of BRD9 PROTAC degradation. Through molecular docking, binding affinity analysis, and structure-activity relationship study, we identified a highly potent PROTAC E5, with excellent BRD9 degradation (DC50 = 16 pM) and antiproliferation in MV4-11 cells (IC50 = 0.27 nM) and OCI-LY10 cells (IC50 = 1.04 nM). E5 can selectively degrade BRD9 and induce cell cycle arrest and apoptosis. Moreover, the therapeutic efficacy of E5 was confirmed in xenograft tumor models, accompanied by further RNA-seq analysis. Therefore, these results may pave the way and provide the reference for the discovery and investigation of highly effective PROTAC degraders.
Assuntos
Antineoplásicos , Proliferação de Células , Simulação de Acoplamento Molecular , Ubiquitina-Proteína Ligases , Humanos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo , Linhagem Celular Tumoral , Camundongos , Descoberta de Drogas , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Camundongos Nus , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de Xenoenxerto , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas que Contêm BromodomínioRESUMO
Cyclic peptides represent one of the most promising therapeutic agents in drug discovery due to their good affinity and selectivity. Herein, an on-resin synthesis of aryl thioether containing peptides and a concise cyclization strategy via chemoselective cysteine SNAr reaction was developed. The arylation group could be incorporated into a series of amino acids and used for standard SPPS and peptides cyclization. Constructed cyclic peptides showed increased cellular uptakes compared to their linear peptides.
Assuntos
CisteínaRESUMO
The Hippo pathway is an evolutionarily conserved signaling pathway that plays critical roles in the tumorigenesis and progression of breast cancer, oral cancer, rectal cancer, colloid cancer, and so on. YAP/TAZ-TEAD complex is a key knot in the Hippo pathway regulating cell proliferation and stem cell functions. Activation or overexpression of this complex has been proved to lead to cell transformation, proliferation and eventually cancerization. In this review, the association between the alterations of hippo pathway and tumorigenesis of various cancer had been elucidated. The structural basis of YAP/TAZ-TEAD complex is analyzed, and the targeting inhibitors are summarized within the medicinal chemistry classification. Moreover, we have also discussed the clinical status and current challenges of these drug candidates, and provide guidance for the future development of inhibitors targeting this pathway, especially YAP/TAZ-TEAD complex.
Assuntos
Antineoplásicos , Carcinogênese , Via de Sinalização Hippo , Neoplasias , Fatores de Transcrição de Domínio TEA , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Proteínas de Sinalização YAP , Humanos , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Via de Sinalização Hippo/efeitos dos fármacos , Proteínas de Sinalização YAP/antagonistas & inibidores , Proteínas de Sinalização YAP/química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/antagonistas & inibidores , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/química , Fatores de Transcrição de Domínio TEA/antagonistas & inibidores , Fatores de Transcrição de Domínio TEA/química , Conformação Proteica , Complexos Multiproteicos/antagonistas & inibidores , Complexos Multiproteicos/químicaRESUMO
Bruton's tyrosine kinase proteolysis-targeting chimeras (BTK-PROTACs) have emerged as a promising approach to address the limitations of BTK inhibitors. However, conducting the rational discovery of orally bioavailable BTK-PROTACs presents significant challenges. In this study, dimensionality reduction analysis and model molecule validation were utilized to identify some key structural features for improving the oral absorption of BTK-PROTACs. The results were applied to optimize the newly discovered BTK-PROTACs B1 and B2. Compound C13 was discovered with improved oral bioavailability, high BTK degradation activity, and selectivity. It exhibited inhibitory effects against different hematologic cancer cells and attenuated the BTK-related signaling pathway. The oral administration of C13 effectively reduced BTK protein levels and suppressed tumor growth. This study led to the discovery of a new orally bioavailable BTK-PROTAC for the treatment of lymphoma, and we hope that the strategy will find wide utility.
Assuntos
Linfoma , Inibidores de Proteínas Quinases , Tirosina Quinase da Agamaglobulinemia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Linfoma/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Stored-product psocids (Psocoptera: Liposcelididae) are cosmopolitan storage pests that can damage stored products and cause serious economic loss. However, because of the body size (~1 mm) of eggs, nymphs, and adults, morphological identification of most stored-product psocids is difficult and hampers effective identification. In this study, 10 economically important stored-product Liposcelis spp. psocids (Liposcelis brunnea, L. entomophila, L. decolor, L. pearmani, L. rufa, L.mendax, L. bostrychophila, L. corrodens, L. paeta, and L. tricolor) were collected from 25 geographic locations in 3 countries (China, Czech Republic, and the United States). Ten species-specific probes for identifying these 10 psocid species were designed based on ITS2 sequences. The microarray method and reaction system were optimized. Specificity of each of the ten probes was tested, and all probes were found suitable for use in identification of the respective10 Liposcelis spp. psocids at 66 °C. This method was also used to identify an unknown psocid species collected in Taian, China. This work has contributed to the development of a molecular identification method for stored-product psocids, and can provide technical support not only to facilitate identification of intercepted samples in relation to plant quarantine, but also for use in insect pest monitoring.