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1.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072837

RESUMO

The chromatin reader protein Spindlin1 plays an important role in epigenetic regulation, through which it has been linked to several types of malignant tumors. In the current work, we report on the development of novel analogs of the previously published lead inhibitor A366. In an effort to improve the activity and explore the structure-activity relationship (SAR), a series of 21 derivatives was synthesized, tested in vitro, and investigated by means of molecular modeling tools. Docking studies and molecular dynamics (MD) simulations were performed to analyze and rationalize the structural differences responsible for the Spindlin1 activity. The analysis of MD simulations shed light on the important interactions. Our study highlighted the main structural features that are required for Spindlin1 inhibitory activity, which include a positively charged pyrrolidine moiety embedded into the aromatic cage connected via a propyloxy linker to the 2-aminoindole core. Of the latter, the amidine group anchor the compounds into the pocket through salt bridge interactions with Asp184. Different protocols were tested to identify a fast in silico method that could help to discriminate between active and inactive compounds within the A366 series. Rescoring the docking poses with MM-GBSA calculations was successful in this regard. Because A366 is known to be a G9a inhibitor, the most active developed Spindlin1 inhibitors were also tested over G9a and GLP to verify the selectivity profile of the A366 analogs. This resulted in the discovery of diverse selective compounds, among which 1s and 1t showed Spindlin1 activity in the nanomolar range and selectivity over G9a and GLP. Finally, future design hypotheses were suggested based on our findings.


Assuntos
Fenômenos Biofísicos , Proteínas de Ciclo Celular/química , Epigênese Genética , Proteínas Associadas aos Microtúbulos/química , Fosfoproteínas/química , Conformação Proteica , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/ultraestrutura , Entropia , Humanos , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/ultraestrutura , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/genética , Fosfoproteínas/ultraestrutura , Ligação Proteica , Relação Estrutura-Atividade
2.
Angew Chem Int Ed Engl ; 56(41): 12476-12480, 2017 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-28766825

RESUMO

Bromodomain and extra-terminal domain (BET) inhibitors are widely used both as chemical tools to study the biological role of their targets in living organisms and as candidates for drug development against several cancer variants and human disorders. However, non-BET bromodomains such as those in p300 and CBP are less studied. XDM-CBP is a highly potent and selective inhibitor for the bromodomains of CBP and p300 derived from a pan-selective BET BRD-binding fragment. Along with X-ray crystal-structure analysis and thermodynamic profiling, XDM-CBP was used in screenings of several cancer cell lines in vitro to study its inhibitory potential on cancer cell proliferation. XDM-CBP is demonstrated to be a potent and selective CBP/p300 inhibitor that acts on specific cancer cell lines, in particular malignant melanoma, breast cancer, and leukemia.

3.
Future Med Chem ; 8(13): 1537-51, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27572962

RESUMO

AIM: The histone kinase PRK1 has been identified as a potential target to combat prostate cancer but selective PRK1 inhibitors are lacking. The US FDA -approved JAK1-3 inhibitor tofacitinib also potently inhibits PRK1 in vitro. RESULTS: We show that tofacitinib also inhibits PRK1 in a cellular setting. Using tofacitinib as a starting point for structure-activity relationship studies, we identified a more potent and another more selective PRK1 inhibitor compared with tofacitinib. Furthermore, we found two potential PRK1/JAK3-selectivity hotspots. CONCLUSION: The identified inhibitors and the selectivity hotspots lay the basis for the development of selective PRK1 inhibitors. The identification of PRK1, but also of other cellular tofacitinib targets, has implications on its clinical use and on future development of tofacitinib-like JAK inhibitors. [Formula: see text].


Assuntos
Piperidinas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
4.
Data Brief ; 7: 1370-4, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27158652

RESUMO

This article presents detailed purification procedures for the bromodomains BRD3(1), BRD3(2), BRD4(1), and BRPF1B. In addition we provide crystallization protocols for apo BRD4(1) and BRD4(1) in complex with numerous inhibitors. The protocols described here were successfully applied to obtain affinity data by isothermal titration calorimetry (ITC) and by differential scanning fluorimetry (DSF) as well as structural characterizations of BRD4(1) inhibitor complexes (PDB codes: PDB: 4LYI, PDB: 4LZS, PDB: 4LYW, PDB: 4LZR, PDB: 4LYS, PDB: 5D24, PDB: 5D25, PDB: 5D26, PDB: 5D3H, PDB: 5D3J, PDB: 5D3L, PDB: 5D3N, PDB: 5D3P, PDB: 5D3R, PDB: 5D3S, PDB: 5D3T). These data have been reported previously and are discussed in more detail elsewhere [1], [2].

5.
J Med Chem ; 59(4): 1518-30, 2016 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-26731611

RESUMO

Several human diseases, including cancer, show altered signaling pathways resulting from changes in the activity levels of epigenetic modulators. In the past few years, small-molecule inhibitors against specific modulators, including the bromodomain and extra-terminal (BET) bromodomain family of acetylation readers, have shown early promise in the treatment of the genetically defined midline carcinoma and hematopoietic malignancies. We have recently developed a novel potent inhibitor of BET proteins, 1 (XD14[ Angew. Chem., Int. Ed. 2013, 52, 14055]), which exerts a strong inhibitory potential on the proliferation of specific leukemia cell lines. In the study presented here, we designed analogues of 1 to study the potential of substitutions on the 4-acyl pyrrole backbone to occupy additional sites within the substrate recognition site of BRD4(1). The compounds were profiled using ITC, DSF, and X-ray crystallography. We could introduce several substitutions that address previously untargeted areas of the substrate recognition site. This work may substantially contribute to the development of therapeutics with increased target specificity against BRD4-related malignancies.


Assuntos
Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Pirróis/química , Pirróis/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Acilação , Sítios de Ligação , Proteínas de Ciclo Celular , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Proteínas Nucleares/química , Fatores de Transcrição/química
6.
Chemistry ; 20(8): 2164-8, 2014 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-24478039

RESUMO

Homolargazole derivatives, in which the macrocycle of natural largazole is extended by one methylene group, were prepared by the recently developed rhodium-catalyzed hydrocarboxylation reaction onto allenes. This strategy gives access to both the (18S)- and (18R)-stereoisomers in high stereoselectivity under ligand control.


Assuntos
Alcadienos/química , Depsipeptídeos/síntese química , Ródio/química , Tiazóis/síntese química , Catálise , Depsipeptídeos/química , Ligantes , Estrutura Molecular , Estereoisomerismo , Tiazóis/química
7.
J Org Chem ; 76(8): 2899-903, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21395333

RESUMO

The synthesis of 2- and 6-trifluoromethylated purines and 1-deazapurines was performed by formal [3 + 3]-cyclization reactions of 5-aminoimidazoles with a set of trifluoromethyl-substituted 1,3-CCC- and 1,3-CNC-dielectrophiles. The corresponding fluorinated nucleosides were synthesized by glycosylation of 9-unsubstituted purines and 1-deazapurines with peracetylated ß-ribose, ß-glucose, and rhamnose and subsequent deprotection. These scaffolds can be considered as potential inhibitors of adenosine deaminase (ADA) and inosine monophosphate dehydrogenase (IMPDH) enzymes.


Assuntos
Inibidores de Adenosina Desaminase/síntese química , Glicosídeos/síntese química , Purinas/síntese química , Adenosina Desaminase/metabolismo , Inibidores de Adenosina Desaminase/farmacologia , Ciclização , Glicosídeos/farmacologia , Glicosilação , Halogenação , Humanos , IMP Desidrogenase/antagonistas & inibidores , Imidazóis/química , Mimetismo Molecular , Monossacarídeos/química , Purinas/farmacologia
8.
Org Biomol Chem ; 8(23): 5280-4, 2010 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-20938501

RESUMO

The first synthesis of 3-methoxalylchromone was described. The reaction of the latter with electron-rich aminoheterocycles afforded a set of heteroannelated pyridines bearing a CO(2)Me substituent located at the α-position of the pyridine core.


Assuntos
Cromonas/síntese química , Purinas/química , Modelos Moleculares , Estrutura Molecular
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