RESUMO
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) binds to death receptors and induces apoptosis in various cancer cell lines while sparing normal cells. Recombinant TRAIL has shown good safety and efficacy profiles in preclinical cancer models. However, clinical success has been limited due to poor PK and development of resistance to death receptor-induced apoptosis. We have addressed these issues by creating a fusion protein of TRAIL and arginine deiminase (ADI). The fusion protein benefits from structural and functional synergies between its two components and has an extended half-life in vivo. ADI downregulates survivin, upregulates DR5 receptor and sensitizes cancer cells to TRAIL induced apoptosis. ADI-TRAIL fusion protein was efficacious in a number of cell lines and synergized with some standard of care drugs. In an HCT116 xenograft model ADI-TRAIL localized to the tumor and induced dose-dependent tumor regression, the fusion protein was superior to rhTRAIL administered at the same molar amounts.
RESUMO
A series of macrocyclic derivatives has been designed and synthesized based on the X-ray co-crystal structures of pyrazolo[1,5-a] [1,3,5]triazines with corn CK2 (cCK2) protein. Bioassays demonstrated that these macrocyclic pyrazolo[1,5-a] [1,3,5]triazine compounds are potent CK2 inhibitors with K(i) around 1.0 nM and strongly inhibit cancer cell growth with IC(50) as low as approximately 100 nM.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Caseína Quinase II/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Triazinas/química , Triazinas/farmacologia , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Masculino , Conformação Molecular , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/síntese química , Relação Estrutura-Atividade , Triazinas/síntese químicaRESUMO
The structure-based design, synthesis, and anticancer activity of novel inhibitors of protein kinase CK2 are described. Using pyrazolo[1,5-a][1,3,5]triazine as the core scaffold, a structure-guided series of modifications provided pM inhibitors with microM-level cytotoxic activity in cell-based assays with prostate and colon cancer cell lines.
Assuntos
Caseína Quinase II/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Sítios de Ligação , Caseína Quinase II/metabolismo , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese químicaRESUMO
The design, synthesis, and biological evaluation of potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) are reported. A novel series of 3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-ones were designed using a combination of protein structure-based drug design, molecular modeling, and structure-activity relationships (SAR). These novel submicromolar inhibitors possess a tricyclic ring system conformationally restricting the benzamide in the preferred cis orientation. The compounds were designed to optimize space-filling and atomic interactions within the NAD+ binding site of PARP-1. Previously described and newly adapted methods were applied to syntheses of these tricyclic inhibitors. Various modifications were made to the diazepinoindolones at the 6- and 7-positions in order to study this region of the active site and optimize noncovalent interactions. The electron density of derivative 28 bound to chicken PARP-1 revealed that the oxime makes a tight hydrogen bond with the catalytic gamma-carboxylate of glutamic acid (Glu) 988 in accordance with our original designs and models. Most of the compounds have been evaluated for inhibition of human PARP-1. Selected inhibitors were also tested for the ability to potentiate the cytotoxic effect of the DNA-damaging agent Topotecan.
Assuntos
Antineoplásicos/síntese química , Azepinas/síntese química , Indóis/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases , Antineoplásicos/química , Antineoplásicos/farmacologia , Azepinas/química , Azepinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Humanos , Indóis/química , Indóis/farmacologia , Modelos Moleculares , Relação Estrutura-Atividade , Inibidores da Topoisomerase IRESUMO
The structure-based design, synthesis, and biological activity of novel inhibitors of S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase are described. Using 6-substituted purine and deaza purines as the core scaffolds, a systematic and structure guided series of modifications provided low nM inhibitors with broad-spectrum antimicrobial activity.
Assuntos
Antibacterianos/síntese química , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , N-Glicosil Hidrolases/antagonistas & inibidores , Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Homocisteína/antagonistas & inibidores , Homocisteína/metabolismo , N-Glicosil Hidrolases/metabolismo , Purina-Núcleosídeo Fosforilase/antagonistas & inibidores , Purina-Núcleosídeo Fosforilase/metabolismo , Purinas/síntese química , Purinas/farmacologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates the repair of DNA strand breaks. Inhibiting PARP-1 increases the cytotoxicity of DNA-damaging chemotherapy and radiation therapy in vitro. Because classical PARP-1 inhibitors have limited clinical utility, we investigated whether AG14361, a novel potent PARP-1 inhibitor (inhibition constant <5 nM), enhances the effects of chemotherapy and radiation therapy in human cancer cell cultures and xenografts. METHODS: The effect of AG14361 on the antitumor activity of the DNA alkylating agent temozolomide, topoisomerase I poisons topotecan or irinotecan, or x-irradiation or gamma-radiation was investigated in human cancer cell lines A549, LoVo, and SW620 by proliferation and survival assays and in xenografts in mice by tumor volume determination. The specificity of AG14361 for PARP-1 was investigated by microarray analysis and by antiproliferation and acute toxicity assays in PARP-1-/- and PARP-1+/+ cells and mice. After intraperitoneal administration, the concentration of AG14361 was determined in mouse plasma and tissues, and its effect on PARP-1 activity was determined in tumor homogenates. All statistical tests were two-sided. RESULTS: AG14361 at 0.4 micro M did not affect cancer cell gene expression or growth, but it did increase the antiproliferative activity of temozolomide (e.g., in LoVo cells by 5.5-fold, 95% confidence interval [CI] = 4.9-fold to 5.9-fold; P =.004) and topotecan (e.g., in LoVo cells by 1.6-fold, 95% CI = 1.3-fold to 1.9-fold; P =.002) and inhibited recovery from potentially lethal gamma-radiation damage in LoVo cells by 73% (95% CI = 48% to 98%). In vivo, nontoxic doses of AG14361 increased the delay of LoVo xenograft growth induced by irinotecan, x-irradiation, or temozolomide by two- to threefold. The combination of AG14361 and temozolomide caused complete regression of SW620 xenograft tumors. AG14361 was retained in xenografts in which PARP-1 activity was inhibited by more than 75% for at least 4 hours. CONCLUSION: AG14361 is, to our knowledge, the first high-potency PARP-1 inhibitor with the specificity and in vivo activity to enhance chemotherapy and radiation therapy of human cancer.
Assuntos
Antineoplásicos/farmacologia , Benzodiazepinas/farmacologia , Dacarbazina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Radiossensibilizantes/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Azulenos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/radioterapia , Dacarbazina/farmacologia , Raios gama/uso terapêutico , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Camundongos , Poli(ADP-Ribose) Polimerases/metabolismo , Temozolomida , Transplante HeterólogoRESUMO
The structure-based design, synthesis, and biological activity of a novel indazole-containing inhibitor series for S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase are described. Use of 5-aminoindazole as the core scaffold provided a structure-guided series of low nanomolar inhibitors with broad-spectrum antimicrobial activity. The implementation of structure-based methodologies provided a 6000-fold increase in potency over a short timeline (several months) and an economy of synthesized compounds.
Assuntos
Antibacterianos/síntese química , Indazóis/síntese química , N-Glicosil Hidrolases/antagonistas & inibidores , Sulfonamidas/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Indazóis/química , Indazóis/farmacologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , N-Glicosil Hidrolases/química , Neisseria meningitidis/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
Novel tricyclic benzimidazole carboxamide poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been synthesized. Several compounds were found to be powerful chemopotentiators of temozolomide and topotecan in both A549 and LoVo cell lines. In vitro inhibition of PARP-1 was confirmed by direct measurement of NAD+ depletion and ADP-ribose polymer formation caused by chemically induced DNA damage.
Assuntos
Benzimidazóis/síntese química , Dacarbazina/análogos & derivados , Inibidores Enzimáticos/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Dacarbazina/metabolismo , Dacarbazina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Modelos Moleculares , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Temozolomida , Topotecan/metabolismo , Topotecan/farmacologiaRESUMO
A series of novel compounds have been designed that are potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1), and the activity and physical properties have been characterized. The new structural classes, 3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-ones and 3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5-(1H)-ones, have conformationally locked benzamide cores that specifically interact with the PARP-1 protein. The compounds have been evaluated with in vitro cellular assays that measure the ability of the PARP-1 inhibitors to enhance the effect of cytotoxic agents against cancer cell lines.