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1.
Nature ; 628(8007): 433-441, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38509368

RESUMO

An important advance in cancer therapy has been the development of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of homologous recombination (HR)-deficient cancers1-6. PARP inhibitors trap PARPs on DNA. The trapped PARPs are thought to block replisome progression, leading to formation of DNA double-strand breaks that require HR for repair7. Here we show that PARP1 functions together with TIMELESS and TIPIN to protect the replisome in early S phase from transcription-replication conflicts. Furthermore, the synthetic lethality of PARP inhibitors with HR deficiency is due to an inability to repair DNA damage caused by transcription-replication conflicts, rather than by trapped PARPs. Along these lines, inhibiting transcription elongation in early S phase rendered HR-deficient cells resistant to PARP inhibitors and depleting PARP1 by small-interfering RNA was synthetic lethal with HR deficiency. Thus, inhibiting PARP1 enzymatic activity may suffice for treatment efficacy in HR-deficient settings.


Assuntos
Replicação do DNA , Inibidores de Poli(ADP-Ribose) Polimerases , Poli(ADP-Ribose) Polimerases , Transcrição Gênica , Humanos , Quebras de DNA de Cadeia Dupla , Replicação do DNA/efeitos dos fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Reparo de DNA por Recombinação , Fase S , Transcrição Gênica/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Poli(ADP-Ribose) Polimerase-1/metabolismo
2.
ACS Med Chem Lett ; 13(3): 499-506, 2022 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-35300078

RESUMO

Multitarget directed ligands (MTDLs) represent a promising frontier in tackling the complexity of multifactorial pathologies. The synergistic inhibition of monoamine oxidase B (MAO B) and acetylcholinesterase (AChE) is believed to provide a potentiated effect in the treatment of Alzheimer's disease. Among previously reported micromolar or sub-micromolar coumarin-bearing dual inhibitors, compound 1 returned a tight-binding inhibition of MAO B (K i = 4.5 µM) and a +5.5 °C increase in the enzyme T m value. Indeed, the X-ray crystal structure revealed that binding of 1 produces unforeseen conformational changes at the MAO B entrance cavity. Interestingly, 1 showed great shape complementarity with the AChE enzymatic gorge, being deeply buried from the catalytic anionic subsite (CAS) to the peripheral anionic subsite (PAS) and causing significant structural changes in the active site. These findings provide structural templates for further development of dual MAO B and AChE inhibitors.

3.
ACS Med Chem Lett ; 12(7): 1151-1158, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34262643

RESUMO

A library of monosubstituted chalcones (1-17) bearing electron-donating and electron-withdrawing groups on both aromatic rings were selected. The cell viability on human tumor cell lines was evaluated first. The compounds unable to induce detectable cytotoxicity (1, 13, and 14) were tested using the monoamine oxidase (MAO) activity assay. Interestingly, they inhibit MAO-B, acting as competitive inhibitors, with 13 and 14 showing the best profiles. In particular, 13 exhibited a potency higher than that of safinamide, taken as a reference. Docking studies and crystallographic analysis showed that in human MAO-B 13 binds with the halogen-substituted aromatic ring in the entrance cavity, similar to safinamide, whereas 14 is accommodated in the opposite way. The main conclusion of this cell biology, biochemistry, and structural study is to highlights 13 as a chalcone derivative that is worth consideration for the development of novel MAO-B-selective inhibitors for the treatment of neurodegenerative diseases.

4.
ChemMedChem ; 15(15): 1394-1397, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32459875

RESUMO

Diphenylene iodonium (DPI) is known for its inhibitory activities against many flavin- and heme-dependent enzymes, and is often used as an NADPH oxidase inhibitor. We probed the efficacy of DPI on two well-known drug targets, the human monoamine oxidases MAO A and B. UV-visible spectrophotometry and steady-state kinetics experiments demonstrate that DPI acts as a competitive and reversible MAO inhibitor with Ki values of 1.7 and 0.3 µM for MAO A and MAO B, respectively. Elucidation of the crystal structure of human MAO B bound to the inhibitor revealed that DPI binds deeply in the active-site cavity to establish multiple hydrophobic interactions with the surrounding side chains and the flavin. These data prove that DPI is a genuine MAO inhibitor and that the inhibition mechanism does not involve a reaction with the reduced flavin. This binding and inhibitory activity against the MAOs, two major reactive oxygen species (ROS)-producing enzymes, will have to be carefully considered when interpreting experiments that rely on DPI for target validation and chemical biology studies on ROS functions.


Assuntos
Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores da Monoaminoxidase/química , Oniocompostos , Relação Estrutura-Atividade
5.
J Med Chem ; 63(3): 1361-1387, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31917923

RESUMO

The resurgence of interest in monoamine oxidases (MAOs) has been fueled by recent correlations of this enzymatic activity with cardiovascular, neurological, and oncological disorders. This has promoted increased research into selective MAO-A and MAO-B inhibitors. Here, we shed light on how selective inhibition of MAO-A and MAO-B can be achieved by geometric isomers of cis- and trans-1-propargyl-4-styrylpiperidines. While the cis isomers are potent human MAO-A inhibitors, the trans analogues selectively target only the MAO-B isoform. The inhibition was studied by kinetic analysis, UV-vis spectrum measurements, and X-ray crystallography. The selective inhibition of the MAO-A and MAO-B isoforms was confirmed ex vivo in mouse brain homogenates, and additional in vivo studies in mice show the therapeutic potential of 1-propargyl-4-styrylpiperidines for central nervous system disorders. This study represents a unique case of stereoselective activity of cis/trans isomers that can discriminate between structurally related enzyme isoforms.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Inibidores da Monoaminoxidase/uso terapêutico , Piperidinas/uso terapêutico , Estirenos/uso terapêutico , Animais , Antidepressivos/síntese química , Antidepressivos/metabolismo , Encéfalo , Domínio Catalítico , Humanos , Isoenzimas/antagonistas & inibidores , Cinética , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Monoaminoxidase/química , Monoaminoxidase/classificação , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/metabolismo , Piperidinas/síntese química , Piperidinas/metabolismo , Ligação Proteica , Estereoisomerismo , Relação Estrutura-Atividade , Estirenos/síntese química , Estirenos/metabolismo
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