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1.
J Med Chem ; 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34648286

RESUMO

USP5 is a deubiquitinase that has been implicated in a range of diseases, including cancer, but no USP5-targeting chemical probe has been reported to date. Here, we present the progression of a chemical series that occupies the C-terminal ubiquitin-binding site of a poorly characterized zinc-finger ubiquitin binding domain (ZnF-UBD) of USP5 and competitively inhibits the catalytic activity of the enzyme. Exploration of the structure-activity relationship, complemented with crystallographic characterization of the ZnF-UBD bound to multiple ligands, led to the identification of 64, which binds to the USP5 ZnF-UBD with a KD of 2.8 µM and is selective over nine proteins containing structurally similar ZnF-UBD domains. 64 inhibits the USP5 catalytic cleavage of a di-ubiquitin substrate in an in vitro assay. This study provides a chemical and structural framework for the discovery of a chemical probe to delineate USP5 function in cells.

2.
Nat Commun ; 12(1): 4848, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381037

RESUMO

There is currently a lack of effective drugs to treat people infected with SARS-CoV-2, the cause of the global COVID-19 pandemic. The SARS-CoV-2 Non-structural protein 13 (NSP13) has been identified as a target for anti-virals due to its high sequence conservation and essential role in viral replication. Structural analysis reveals two "druggable" pockets on NSP13 that are among the most conserved sites in the entire SARS-CoV-2 proteome. Here we present crystal structures of SARS-CoV-2 NSP13 solved in the APO form and in the presence of both phosphate and a non-hydrolysable ATP analog. Comparisons of these structures reveal details of conformational changes that provide insights into the helicase mechanism and possible modes of inhibition. To identify starting points for drug development we have performed a crystallographic fragment screen against NSP13. The screen reveals 65 fragment hits across 52 datasets opening the way to structure guided development of novel antiviral agents.


Assuntos
Metiltransferases/química , RNA Helicases/química , SARS-CoV-2/química , Proteínas não Estruturais Virais/química , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Sequência de Aminoácidos , Apoenzimas/química , Apoenzimas/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Metiltransferases/antagonistas & inibidores , Metiltransferases/metabolismo , Modelos Moleculares , Fosfatos/química , Fosfatos/metabolismo , Conformação Proteica , RNA Helicases/antagonistas & inibidores , RNA Helicases/metabolismo , RNA Viral/química , RNA Viral/metabolismo , SARS-CoV-2/enzimologia , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo
3.
SLAS Discov ; 26(9): 1200-1211, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34192965

RESUMO

The COVID-19 pandemic has clearly brought the healthcare systems worldwide to a breaking point, along with devastating socioeconomic consequences. The SARS-CoV-2 virus, which causes the disease, uses RNA capping to evade the human immune system. Nonstructural protein (nsp) 14 is one of the 16 nsps in SARS-CoV-2 and catalyzes the methylation of the viral RNA at N7-guanosine in the cap formation process. To discover small-molecule inhibitors of nsp14 methyltransferase (MTase) activity, we developed and employed a radiometric MTase assay to screen a library of 161 in-house synthesized S-adenosylmethionine (SAM) competitive MTase inhibitors and SAM analogs. Among six identified screening hits, SS148 inhibited nsp14 MTase activity with an IC50 value of 70 ± 6 nM and was selective against 20 human protein lysine MTases, indicating significant differences in SAM binding sites. Interestingly, DS0464 with an IC50 value of 1.1 ± 0.2 µM showed a bisubstrate competitive inhibitor mechanism of action. DS0464 was also selective against 28 out of 33 RNA, DNA, and protein MTases. The structure-activity relationship provided by these compounds should guide the optimization of selective bisubstrate nsp14 inhibitors and may provide a path toward a novel class of antivirals against COVID-19, and possibly other coronaviruses.


Assuntos
COVID-19/genética , Exorribonucleases/genética , Ligação Proteica/genética , SARS-CoV-2/genética , Proteínas não Estruturais Virais/genética , Antivirais/farmacologia , Sítios de Ligação/genética , COVID-19/virologia , Humanos , Metilação , Pandemias , RNA Viral/genética , SARS-CoV-2/patogenicidade , Replicação Viral/genética
4.
J Proteome Res ; 20(8): 4212-4215, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34180678

RESUMO

In the absence of effective treatment, COVID-19 is likely to remain a global disease burden. Compounding this threat is the near certainty that novel coronaviruses with pandemic potential will emerge in years to come. Pan-coronavirus drugs-agents active against both SARS-CoV-2 and other coronaviruses-would address both threats. A strategy to develop such broad-spectrum inhibitors is to pharmacologically target binding sites on SARS-CoV-2 proteins that are highly conserved in other known coronaviruses, the assumption being that any selective pressure to keep a site conserved across past viruses will apply to future ones. Here we systematically mapped druggable binding pockets on the experimental structure of 15 SARS-CoV-2 proteins and analyzed their variation across 27 α- and ß-coronaviruses and across thousands of SARS-CoV-2 samples from COVID-19 patients. We find that the two most conserved druggable sites are a pocket overlapping the RNA binding site of the helicase nsp13 and the catalytic site of the RNA-dependent RNA polymerase nsp12, both components of the viral replication-transcription complex. We present the data on a public web portal (https://www.thesgc.org/SARSCoV2_pocketome/), where users can interactively navigate individual protein structures and view the genetic variability of drug-binding pockets in 3D.


Assuntos
COVID-19 , SARS-CoV-2 , Antivirais/farmacologia , Antivirais/uso terapêutico , Humanos , Pandemias , RNA Polimerase Dependente de RNA/genética
5.
ACS Chem Biol ; 16(4): 579-585, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33745272

RESUMO

Chemical probes are selective modulators that are used in cell assays to link a phenotype to a gene and have become indispensable tools to explore gene function and discover therapeutic targets. Chemical probe off-targets are a confounding factor as the observed phenotype may be driven by inhibition of an unknown off-target instead of the targeted protein. A negative control, a close chemical analog of the chemical probe that is inactive against the intended target, is typically used to verify that the phenotype is indeed driven by the targeted protein. Here, we compare the selectivity profiles of four unrelated chemical probes and their respective negative controls. We find that controls that chemically deviate from the probe by a single heavy atom can be inactive against up to 80% of known off-targets if the chemical modification has a charge-neutralizing effect. In such cases, a loss in phenotype upon treatment with the negative control may be driven by loss of inhibition of an off-target. To expand this analysis, we inspect the crystal structures of 90 pairs of unrelated proteins, where both proteins within each pair is in complex with the same drug-like ligand. We computationally estimate that in 50% of cases, methylation of the ligand (a simple chemical modification often used to generate negative controls) at a position that will preclude binding to one protein (the intended target) will also preclude binding to the other (the off-target). These results emphasize the need to select negative controls with care and profile both chemical probes and negative controls against diverse protein arrays to verify that off-targets of probes are also hit by negative controls. When available, a best practice should be to verify that two unrelated chemical probes targeting the same protein elicit the same phenotype.


Assuntos
Sondas Moleculares/química , Bibliotecas de Moléculas Pequenas/química , Bases de Dados de Proteínas , Humanos , Ligantes
6.
Nat Rev Drug Discov ; 20(7): 509-530, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33742187

RESUMO

Protein arginine methyltransferases (PRMTs) are emerging as attractive therapeutic targets. PRMTs regulate transcription, splicing, RNA biology, the DNA damage response and cell metabolism; these fundamental processes are altered in many diseases. Mechanistically understanding how these enzymes fuel and sustain cancer cells, especially in specific metabolic contexts or in the presence of certain mutations, has provided the rationale for targeting them in oncology. Ongoing inhibitor development, facilitated by structural biology, has generated tool compounds for the majority of PRMTs and enabled clinical programmes for the most advanced oncology targets, PRMT1 and PRMT5. In-depth mechanistic investigations using genetic and chemical tools continue to delineate the roles of PRMTs in regulating immune cells and cancer cells, and cardiovascular and neuronal function, and determine which pathways involving PRMTs could be synergistically targeted in combination therapies for cancer. This research is enhancing our knowledge of the complex functions of arginine methylation, will guide future clinical development and could identify new clinical indications.


Assuntos
Arginina/metabolismo , Sistemas de Liberação de Medicamentos , Proteína-Arginina N-Metiltransferases/metabolismo , Animais , Descoberta de Drogas , Inibidores Enzimáticos/uso terapêutico , Humanos , Metilação , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteínas/metabolismo
7.
J Med Chem ; 64(3): 1584-1592, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33522809

RESUMO

Increased activity of the lysine methyltransferase NSD2 driven by translocation and activating mutations is associated with multiple myeloma and acute lymphoblastic leukemia, but no NSD2-targeting chemical probe has been reported to date. Here, we present the first antagonists that block the protein-protein interaction between the N-terminal PWWP domain of NSD2 and H3K36me2. Using virtual screening and experimental validation, we identified the small-molecule antagonist 3f, which binds to the NSD2-PWWP1 domain with a Kd of 3.4 µM and abrogates histone H3K36me2 binding to the PWWP1 domain in cells. This study establishes an alternative approach to targeting NSD2 and provides a small-molecule antagonist that can be further optimized into a chemical probe to better understand the cellular function of this protein.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Proteínas Repressoras/antagonistas & inibidores , Simulação por Computador , Cristalografia por Raios X , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Histona-Lisina N-Metiltransferase/efeitos dos fármacos , Humanos , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Domínios Proteicos , Proteínas Repressoras/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade
8.
J Med Chem ; 64(7): 3697-3706, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33591753

RESUMO

Protein arginine methyltransferase 6 (PRMT6) catalyzes monomethylation and asymmetric dimethylation of arginine residues in various proteins, plays important roles in biological processes, and is associated with multiple cancers. To date, a highly selective PRMT6 inhibitor has not been reported. Here we report the discovery and characterization of a first-in-class, highly selective allosteric inhibitor of PRMT6, (R)-2 (SGC6870). (R)-2 is a potent PRMT6 inhibitor (IC50 = 77 ± 6 nM) with outstanding selectivity for PRMT6 over a broad panel of other methyltransferases and nonepigenetic targets. Notably, the crystal structure of the PRMT6-(R)-2 complex and kinetic studies revealed (R)-2 binds a unique, induced allosteric pocket. Additionally, (R)-2 engages PRMT6 and potently inhibits its methyltransferase activity in cells. Moreover, (R)-2's enantiomer, (S)-2 (SGC6870N), is inactive against PRMT6 and can be utilized as a negative control. Collectively, (R)-2 is a well-characterized PRMT6 chemical probe and a valuable tool for further investigating PRMT6 functions in health and disease.


Assuntos
Benzodiazepinonas/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Regulação Alostérica , Sítio Alostérico , Benzodiazepinonas/síntese química , Benzodiazepinonas/metabolismo , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Células HEK293 , Humanos , Proteínas Nucleares/metabolismo , Ligação Proteica , Proteína-Arginina N-Metiltransferases/metabolismo , Estereoisomerismo
9.
Neuropsychopharmacology ; 46(2): 413-422, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33036015

RESUMO

The endocannabinoid system (eCBs) encompasses the endocannabinoids, their synthetic and degradative enzymes, and cannabinoid (CB) receptors. The eCBs mediates inhibition of neurotransmitter release and acts as a major homeostatic system. Many aspects of the eCBs are altered in a number of psychiatric disorders including schizophrenia, which is characterized by dysregulation of dopaminergic signaling. The GluN1-Knockdown (GluN1KD) and Dopamine Transporter Knockout (DATKO) mice are models of hyperdopaminergia, which display abnormal psychosis-related behaviors, including hyperlocomotion and changes in pre-pulse inhibition (PPI). Here, we investigate the ability of a novel CB1 receptor (CB1R) allosteric modulator, ABM300, to ameliorate these dysregulated behaviors. ABM300 was characterized in vitro (receptor binding, ß-arrestin2 recruitment, ERK1/2 phosphorylation, cAMP inhibition) and in vivo (anxiety-like behaviors, cannabimimetic effects, novel environment exploratory behavior, pre-pulse inhibition, conditioned avoidance response) to assess the effects of the compound in dysregulated behaviors within the transgenic models. In vitro, ABM300 increased CB1R agonist binding but acted as an inhibitor of CB1R agonist induced signaling, including ß-arrestin2 translocation, ERK phosphorylation and cAMP inhibition. In vivo, ABM300 did not elicit anxiogenic-like or cannabimimetic effects, but it decreased novelty-induced hyperactivity, exaggerated stereotypy, and vertical exploration in both transgenic models of hyperdopaminergia, as well as normalizing PPI in DATKO mice. The data demonstrate for the first time that a CB1R allosteric modulator ameliorates the behavioral deficits in two models of increased dopamine, warranting further investigation as a potential therapeutic target in psychiatry.


Assuntos
Canabinoides , Endofenótipos , Animais , Camundongos , Camundongos Knockout , Receptor CB1 de Canabinoide/genética , Receptores de Canabinoides , Roedores
12.
Drug Discov Today ; 25(3): 561-567, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32084498

RESUMO

International efforts are underway to develop chemical probes for specific protein families, and a 'Target 2035' call to expand these efforts towards a comprehensive chemical coverage of the druggable human genome was recently announced. But what is the druggable genome? Here, we systematically review structures of proteins bound to drug-like ligands available from the Protein Data Bank (PDB) and use ligand desolvation upon binding as a druggability metric to draw a landscape of the human druggable genome. The vast majority of druggable protein families, including some highly populated and disease-associated families, are almost orphan of small-molecule ligands. We propose a list of 46 druggable domains representing 3440 human proteins that could be the focus of large chemical probe discovery efforts.

13.
Nat Commun ; 10(1): 5759, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848333

RESUMO

PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Here we report the discovery of MRK-740, a potent (IC50: 80 ± 16 nM), selective and cell-active PRDM9 inhibitor (Chemical Probe). MRK-740 binds in the substrate-binding pocket, with unusually extensive interactions with the cofactor S-adenosylmethionine (SAM), conferring SAM-dependent substrate-competitive inhibition. In cells, MRK-740 specifically and directly inhibits H3K4 methylation at endogenous PRDM9 target loci, whereas the closely related inactive control compound, MRK-740-NC, does not. The discovery of MRK-740 as a chemical probe for the PRDM subfamily of methyltransferases highlights the potential for exploiting SAM in targeting SAM-dependent methyltransferases.


Assuntos
Descoberta de Drogas/métodos , Inibidores Enzimáticos/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Sondas Moleculares/farmacologia , Cristalografia por Raios X , Metilação de DNA/efeitos dos fármacos , Inibidores Enzimáticos/química , Células HEK293 , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/ultraestrutura , Histonas/metabolismo , Humanos , Concentração Inibidora 50 , Simulação de Dinâmica Molecular , Sondas Moleculares/química , Domínios Proteicos , S-Adenosilmetionina/metabolismo
14.
Molecules ; 24(24)2019 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-31817960

RESUMO

Protein methyltransferases (PMTs) are enzymes involved in epigenetic mechanisms, DNA repair, and other cellular machineries critical to cellular identity and function, and are an important target class in chemical biology and drug discovery. Central to the enzymatic reaction is the transfer of a methyl group from the cofactor S-adenosylmethionine (SAM) to a substrate protein. Here we review how the essentiality of SAM for catalysis is exploited by chemical inhibitors. Occupying the cofactor binding pocket to compete with SAM can be hindered by the hydrophilic nature of this site, but structural studies of compounds now in the clinic revealed that inhibitors could either occupy juxtaposed pockets to overlap minimally, but sufficiently with the bound cofactor, or induce large conformational remodeling leading to a more druggable binding site. Rather than competing with the cofactor, other inhibitors compete with the substrate and rely on bound SAM, either to allosterically stabilize the substrate binding site, or for direct SAM-inhibitor interactions.


Assuntos
Inibidores Enzimáticos/química , Epigênese Genética , Metiltransferases/química , S-Adenosilmetionina/química , Sítios de Ligação , Catálise , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Metiltransferases/antagonistas & inibidores , Modelos Moleculares , Domínios Proteicos/efeitos dos fármacos
15.
Nat Rev Drug Discov ; 18(12): 949-963, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31666732

RESUMO

Proteolysis-targeting chimeras (PROTACs) and related molecules that induce targeted protein degradation by the ubiquitin-proteasome system represent a new therapeutic modality and are the focus of great interest, owing to potential advantages over traditional occupancy-based inhibitors with respect to dosing, side effects, drug resistance and modulating 'undruggable' targets. However, the technology is still maturing, and the design elements for successful PROTAC-based drugs are currently being elucidated. Importantly, fewer than 10 of the more than 600 E3 ubiquitin ligases have so far been exploited for targeted protein degradation, and expansion of knowledge in this area is a key opportunity. Here, we briefly discuss lessons learned about targeted protein degradation in chemical biology and drug discovery and systematically review the expression profile, domain architecture and chemical tractability of human E3 ligases that could expand the toolbox for PROTAC discovery.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Proteólise/efeitos dos fármacos , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Humanos , Neoplasias/metabolismo , Neoplasias/patologia
16.
Nat Struct Mol Biol ; 26(10): 863-869, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31582844

RESUMO

Chromatin regulatory proteins are increasingly recognized as potential new drug targets. Many of these proteins harbor one or more so called 'reader domains' that recognize covalent modifications of lysine and arginine residues, typically on histones, which mediate specific interactions within chromatin. Here we review recent progress in the discovery of drug-like small molecules that antagonize the function of methyl-lysine and methyl-arginine reader domains (Royal family, plant homeodomain (PHD) and WD40 domains) as well as the acyl-lysine-binding YEATS domain.


Assuntos
Cromatina/metabolismo , Descoberta de Drogas/métodos , Código das Histonas/efeitos dos fármacos , Histonas/metabolismo , Animais , Cromatina/química , Histonas/química , Humanos , Modelos Moleculares , Domínios Proteicos/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia
17.
J Med Chem ; 62(22): 10144-10155, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31663737

RESUMO

USP5 disassembles unanchored polyubiquitin chains to recycle free monoubiquitin, and is one of the 12 ubiquitin specific proteases featuring a zinc finger ubiquitin-binding domain (ZnF-UBD). This distinct structural module has been associated with substrate positioning or allosteric modulation of catalytic activity, but its cellular function remains unclear. We screened a chemical library focused on the ZnF-UBD of USP5, crystallized hits in complex with the protein, and generated a preliminary structure-activity relationship, which enables the development of more potent and selective compounds. This work serves as a framework for the discovery of a chemical probe to delineate the function of USP5 ZnF-UBD in proteasomal degradation and other ubiquitin signaling pathways in health and disease.


Assuntos
Endopeptidases/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Bibliotecas de Moléculas Pequenas/química , Ubiquitina/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Endopeptidases/química , Endopeptidases/genética , Espectroscopia de Ressonância Magnética , Domínios Proteicos , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície , Dedos de Zinco
18.
F1000Res ; 8: 87, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31448096

RESUMO

The fundamental goal of the growing open science movement is to increase the efficiency of the global scientific community and accelerate progress and discoveries for the common good. Central to this principle is the rapid disclosure of research outputs in open-access peer-reviewed journals and on pre-print servers. The next bold step in this direction is open laboratory notebooks, where research scientists share their research - including detailed protocols, negative and positive results - online and in near-real-time to synergize with their peers. Here, we highlight the benefits of open lab notebooks to science, society and scientists, and discuss the challenges that this nascent movement is facing. We also present the implementation and progress of our own initiative at openlabnotebooks.org, with more than 20 active contributors after one year of operation.


Assuntos
Laboratórios , Revisão por Pares
19.
J Med Chem ; 62(17): 7669-7683, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31415173

RESUMO

The first chemical probe to primarily occupy the co-factor binding site of a Su(var)3-9, enhancer of a zeste, trithorax (SET) domain containing protein lysine methyltransferase (PKMT) is reported. Protein methyltransferases require S-adenosylmethionine (SAM) as a co-factor (methyl donor) for enzymatic activity. However, SAM itself represents a poor medicinal chemistry starting point for a selective, cell-active inhibitor given its extreme physicochemical properties and its role in multiple cellular processes. A previously untested medicinal chemistry strategy of deliberate file enrichment around molecules bearing the hallmarks of SAM, but with improved lead-like properties from the outset, yielded viable hits against SET and MYND domain-containing protein 2 (SMYD2) that were shown to bind in the co-factor site. These leads were optimized to identify a highly biochemically potent, PKMT-selective, and cell-active chemical probe. While substrate-based inhibitors of PKMTs are known, this represents a novel, co-factor-derived strategy for the inhibition of SMYD2 which may also prove applicable to lysine methyltransferase family members previously thought of as intractable.


Assuntos
Inibidores Enzimáticos/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , S-Adenosilmetionina/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Histona-Lisina N-Metiltransferase/isolamento & purificação , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , S-Adenosilmetionina/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
20.
Bioorg Med Chem ; 27(17): 3866-3878, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31327677

RESUMO

SET domain bifurcated protein 1 (SETDB1) is a human histone-lysine methyltransferase which is amplified in human cancers and was shown to be crucial in the growth of non-small and small cell lung carcinoma. In addition to its catalytic domain, SETDB1 harbors a unique tandem tudor domain which recognizes histone sequences containing both methylated and acetylated lysines, and likely contributes to its localization on chromatin. Using X-ray crystallography and NMR spectroscopy fragment screening approaches, we have identified the first small molecule fragment hits that bind to histone peptide binding groove of the Tandem Tudor Domain (TTD) of SETDB1. Herein, we describe the binding modes of these fragments and analogues and the biophysical characterization of key compounds. These confirmed small molecule fragments will inform the development of potent antagonists of SETDB1 interaction with histones.


Assuntos
Inibidores Enzimáticos/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Histona-Lisina N-Metiltransferase/isolamento & purificação , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/antagonistas & inibidores , Histonas/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Domínio Tudor/efeitos dos fármacos
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