RESUMO
DNA-dependent protein kinase (DNA-PK) is a critical player in the DNA damage response (DDR) and instrumental in the non-homologous end-joining pathway (NHEJ) used to detect and repair DNA double-strand breaks (DSBs). We demonstrate that the potent and highly selective DNA-PK inhibitor, AZD7648, is an efficient sensitizer of radiation- and doxorubicin-induced DNA damage, with combinations in xenograft and patient-derived xenograft (PDX) models inducing sustained regressions. Using ATM-deficient cells, we demonstrate that AZD7648, in combination with the PARP inhibitor olaparib, increases genomic instability, resulting in cell growth inhibition and apoptosis. AZD7648 enhanced olaparib efficacy across a range of doses and schedules in xenograft and PDX models, enabling sustained tumour regression and providing a clear rationale for its clinical investigation. Through its differentiated mechanism of action as an NHEJ inhibitor, AZD7648 complements the current armamentarium of DDR-targeted agents and has potential in combination with these agents to achieve deeper responses to current therapies.
Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Sinergismo Farmacológico , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Piranos/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Triazóis/farmacologia , Células A549 , Animais , Antibióticos Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas , Linhagem Celular Tumoral , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacologia , Instabilidade Genômica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares , Camundongos , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Polietilenoglicóis/farmacologia , Radioterapia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Herein, the synthesis and pharmacological characterization of an extended library of differently substituted N-methyl-14- O-methylmorphinans with natural and unnatural amino acids and three dipeptides at position 6 that emerged as potent µ/δ opioid receptor (MOR/DOR) agonists with peripheral antinociceptive efficacy is reported. The current study adds significant value to our initial structure-activity relationships on a series of zwitterionic analogues of 1 (14- O-methyloxymorphone) by targeting additional amino acid residues. The new derivatives showed high binding and potent agonism at MOR and DOR in vitro. In vivo, the new 6-amino acid- and 6-dipeptide-substituted derivatives of 1 were highly effective in inducing antinociception in the writhing test in mice after subcutaneous administration, which was antagonized by naloxone methiodide demonstrating activation of peripheral opioid receptors. Such peripheral opioid analgesics may represent alternatives to presently available drugs for a safer pain therapy.
Assuntos
Analgésicos Opioides/síntese química , Oximorfona/análogos & derivados , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Analgésicos Opioides/metabolismo , Analgésicos Opioides/uso terapêutico , Animais , Membrana Celular/metabolismo , Dipeptídeos/química , Humanos , Masculino , Camundongos , Morfina/uso terapêutico , Oximorfona/química , Oximorfona/metabolismo , Oximorfona/uso terapêutico , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/patologia , Ligação Proteica , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Relação Estrutura-AtividadeRESUMO
Fluorine-substituted iron(III) salophene complexes (salophene = N,N'-bis(salicylidene)-1,2-phenylenediamine) were synthesized and evaluated for biological activity. All complexes showed growth inhibitory effects with IC50 values ranging from 0.05 to 2.45 µM against HT-29 colon carcinoma as well as MCF-7 and MDA-MB-231 mammary carcinoma cells (cisplatin: 5.75, 12.72, 5.81 µM, respectively). HR-CS MAS investigations revealed that the complexes were highly protein-bound already after an incubation period of 10 min and accumulated more effectively in tumor cells than cisplatin. Interestingly, the ligands were enriched in the cells too, indicating that the salophene moiety acts as a carrier ligand and mediates the uptake of the complexes. Furthermore, induction of apoptosis proved to be dependent on the substitution pattern as well as on the tumor cell line, as evidenced from the annexin V-FITC/PI assay. Most of the complexes, especially the highly active 5-Fe, showed tumor cell specific effects and no/less influence on the proliferation of T-cells generated from the peripheral blood of healthy individuals.
Assuntos
Compostos Férricos/síntese química , Salicilatos/síntese química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , DNA/metabolismo , Compostos Férricos/farmacologia , Flúor , Humanos , Salicilatos/farmacologia , Relação Estrutura-AtividadeRESUMO
A new procedure was elaborated for the synthesis of potentially opioid-active thiazolo- and thiazinomorphinans. These derivatives and some intermediates related with the synthesis were tested in opioid receptor binding studies. Two compounds showed remarkable µ opioid activities and specificities. The ligand-stimulated [(35) S]GTPγS assays confirmed for both compounds the potent full agonist profile at the µ receptor and for the benzothiazinomorphinan derivative also the δ receptor full agonist character. The structures of these remarkably effective compounds were analyzed with the aid of computational chemistry calculations.