RESUMO
Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.
Assuntos
Proteínas de Membrana/agonistas , Nucleotídeos Cíclicos/química , Pirimidinas/química , Administração Intravenosa , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Meia-Vida , Humanos , Imunoterapia , Proteínas de Membrana/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Neoplasias/patologia , Neoplasias/terapia , Nucleotídeos Cíclicos/metabolismo , Nucleotídeos Cíclicos/uso terapêutico , Fosfatos/química , Ratos , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO-TAK-981 adduct as the inhibitory species within the enzyme catalytic site. Optimization of selectivity against related enzymes as well as enhancement of mean residence time of the adduct were critical to the identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect and efficacy in preclinical tumor models, culminating in the identification of the clinical molecule TAK-981.
Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Ácidos Sulfônicos/uso terapêutico , Sumoilação/efeitos dos fármacos , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Humanos , Camundongos , Estrutura Molecular , Ligação Proteica , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Relação Estrutura-Atividade , Ácidos Sulfônicos/síntese química , Ácidos Sulfônicos/metabolismo , Enzimas Ativadoras de Ubiquitina/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Small ubiquitin-like modifier (SUMO) family proteins regulate target-protein functions by post-translational modification. However, a potent and selective inhibitor targeting the SUMO pathway has been lacking. Here we describe ML-792, a mechanism-based SUMO-activating enzyme (SAE) inhibitor with nanomolar potency in cellular assays. ML-792 selectively blocks SAE enzyme activity and total SUMOylation, thus decreasing cancer cell proliferation. Moreover, we found that induction of the MYC oncogene increased the ML-792-mediated viability effect in cancer cells, thus indicating a potential application of SAE inhibitors in treating MYC-amplified tumors. Using ML-792, we further explored the critical roles of SUMOylation in mitotic progression and chromosome segregation. Furthermore, expression of an SAE catalytic-subunit (UBA2) S95N M97T mutant rescued SUMOylation loss and the mitotic defect induced by ML-792, thus confirming the selectivity of ML-792. As a potent and selective SAE inhibitor, ML-792 provides rapid loss of endogenously SUMOylated proteins, thereby facilitating novel insights into SUMO biology.
Assuntos
Inibidores Enzimáticos/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/antagonistas & inibidores , Sumoilação , Proliferação de Células/efeitos dos fármacos , Segregação de Cromossomos/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes myc , Humanos , Mitose/efeitos dos fármacos , Neoplasias/genética , Neoplasias/patologia , Processamento de Proteína Pós-Traducional , Células Tumorais CultivadasRESUMO
Anti-microtubule agents such as paclitaxel and docetaxel have played an important role in the treatment of cancer for many years. Recently, a small molecule that has a taxol-like mode of action (5HPP-33) was reported. Herein, the detailed structure-activity relationship (SAR) studies of 5HPP-33 analogs that are substituted at the isoindole and phenyl rings are described. Bulky substitutions (such as di-isopropyl groups) on the phenyl ring result in the isoindole and phenyl rings being perpendicular to each other. It was found that this conformation is critical for anti-microtubule activity. These studies have provided valuable information, which will be helpful in the design of more potent analogs.
Assuntos
Isoindóis/química , Microtúbulos/química , Paclitaxel/química , Talidomida/análogos & derivados , Talidomida/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Isoindóis/síntese química , Isoindóis/farmacologia , Microtúbulos/metabolismo , Relação Estrutura-Atividade , Talidomida/síntese química , Moduladores de Tubulina/síntese químicaRESUMO
A series of combretastatin A-4 analogs derived from the ATP competitive, VEGF receptor tyrosine kinase inhibitor, SU5416 were synthesized. The cytotoxic effects of the analogs were evaluated against PC-3 and MDA-MB-231 cancer cell lines, as well as their abilities to inhibit tubulin polymerization. Results are compared to those of compound 1, our lead compound previously reported.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Indóis/química , Indóis/farmacologia , Pirróis/química , Pirróis/farmacologia , Estilbenos/química , Estilbenos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/genética , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Isomerismo , Espectroscopia de Ressonância Magnética , Conformação Molecular , Podofilotoxina/farmacologia , Relação Estrutura-Atividade , Tubulina (Proteína)/biossíntese , Tubulina (Proteína)/genéticaRESUMO
We discovered a thalidomide analogue [5-hydroxy-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione (5HPP-33)] with antiproliferative activity against nine cancer cell lines in vitro. Flow cytometric analyses showed that the compound caused G2-M arrest, which occurred mainly at the mitotic phase. In addition, immunofluorescence microscopy and in vitro tubulin polymerization studies showed that 5HPP-33 has antimicrotubule activity with a paclitaxel-like mode of action. It is effective against four different paclitaxel-resistant cell lines. Thus, 5HPP-33 represents a potential antitumor agent.
Assuntos
Antimitóticos/farmacologia , Antineoplásicos/farmacologia , Indóis/farmacologia , Moduladores de Tubulina/farmacologia , Animais , Antimitóticos/síntese química , Antimitóticos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Indóis/síntese química , Indóis/química , Isoindóis , Camundongos , Paclitaxel/farmacologia , Tubulina (Proteína)/efeitos dos fármacos , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaRESUMO
A series of compounds originally derived from the vascular endothelial growth factor receptor tyrosine kinase inhibitor, SU5416, was synthesized and evaluated. The most potent compound in this series, compound 7, structurally resembles the potent anti-microtubule agent Combretastatin A-4, inhibited tubulin polymerization, and showed potent growth inhibitory activities on both prostate and breast cancer lines with IC(50) values in low to subnanomolar range.
Assuntos
Indóis/química , Pirróis/química , Estilbenos/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Divisão Celular/efeitos dos fármacos , Modelos Moleculares , Conformação Molecular , Suínos , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/metabolismoRESUMO
The synthesis and anti-angiogenic activities of linomide and its analogues are reported. Three of the analogues are 3.3-69 times more potent than linomide at inhibiting blood vessel formation in the CAM angiogenesis assay. These compounds possessed considerable anti-proliferative activity against isolated HUVEC cells with no activity against epithelial-derived prostate tumor cells.