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1.
Cell Rep ; 34(3): 108636, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33472061

RESUMO

The chromatin-associated protein WDR5 is a promising pharmacological target in cancer, with most drug discovery efforts directed against an arginine-binding cavity in WDR5 called the WIN site. Despite a clear expectation that WIN site inhibitors will alter the repertoire of WDR5 interaction partners, their impact on the WDR5 interactome remains unknown. Here, we use quantitative proteomics to delineate how the WDR5 interactome is changed by WIN site inhibition. We show that the WIN site inhibitor alters the interaction of WDR5 with dozens of proteins, including those linked to phosphatidylinositol 3-kinase (PI3K) signaling. As proof of concept, we demonstrate that the master kinase PDPK1 is a bona fide high-affinity WIN site binding protein that engages WDR5 to modulate transcription of genes expressed in the G2 phase of the cell cycle. This dataset expands our understanding of WDR5 and serves as a resource for deciphering the action of WIN site inhibitors.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/química , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/genética , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Descoberta de Drogas , Fase G2/genética , Regulação da Expressão Gênica , Células HEK293 , Humanos , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/genética , Modelos Moleculares , Terapia de Alvo Molecular , Ligação Proteica
2.
J Med Chem ; 63(8): 4315-4333, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32223236

RESUMO

The frequent deregulation of MYC and its elevated expression via multiple mechanisms drives cells to a tumorigenic state. Indeed, MYC is overexpressed in up to ∼50% of human cancers and is considered a highly validated anticancer target. Recently, we discovered that WD repeat-containing protein 5 (WDR5) binds to MYC and is a critical cofactor required for the recruitment of MYC to its target genes and reported the first small molecule inhibitors of the WDR5-MYC interaction using structure-based design. These compounds display high binding affinity, but have poor physicochemical properties and are hence not suitable for in vivo studies. Herein, we conducted an NMR-based fragment screening to identify additional chemical matter and, using a structure-based approach, we merged a fragment hit with the previously reported sulfonamide series. Compounds in this series can disrupt the WDR5-MYC interaction in cells, and as a consequence, we observed a reduction of MYC localization to chromatin.


Assuntos
Desenho de Fármacos , Descoberta de Drogas/métodos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-myc/metabolismo , Relação Estrutura-Atividade
3.
J Med Chem ; 63(2): 656-675, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31858797

RESUMO

WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple chromatin-centric processes. Overexpression of WDR5 correlates with a poor clinical outcome in many human cancers, and WDR5 itself has emerged as an attractive target for therapy. Most drug-discovery efforts center on the WIN site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe discovery of a novel WDR5 WIN site antagonists containing a dihydroisoquinolinone bicyclic core using a structure-based design. These compounds exhibit picomolar binding affinity and selective concentration-dependent antiproliferative activities in sensitive MLL-fusion cell lines. Furthermore, these WDR5 WIN site binders inhibit proliferation in MYC-driven cancer cells and reduce MYC recruitment to chromatin at MYC/WDR5 co-bound genes. Thus, these molecules are useful probes to study the implication of WDR5 inhibition in cancers and serve as a potential starting point toward the discovery of anti-WDR5 therapeutics.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Quinolonas/síntese química , Quinolonas/farmacologia , Repetições WD40/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Cromatina/efeitos dos fármacos , Cromatina/genética , Cristalografia por Raios X , Desenho de Fármacos , Descoberta de Drogas , Repressão Epigenética/efeitos dos fármacos , Genes myc/efeitos dos fármacos , Humanos , Relação Estrutura-Atividade
4.
J Med Chem ; 62(24): 11232-11259, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31724864

RESUMO

The treatment of tumors driven by overexpression or amplification of MYC oncogenes remains a significant challenge in drug discovery. Here, we present a new strategy toward the inhibition of MYC via the disruption of the protein-protein interaction between MYC and its chromatin cofactor WD Repeat-Containing Protein 5. Blocking the association of these proteins is hypothesized to disrupt the localization of MYC to chromatin, thus disrupting the ability of MYC to sustain tumorigenesis. Utilizing a high-throughput screening campaign and subsequent structure-guided design, we identify small-molecule inhibitors of this interaction with potent in vitro binding affinity and report structurally related negative controls that can be used to study the effect of this disruption. Our work suggests that disruption of this protein-protein interaction may provide a path toward an effective approach for the treatment of multiple tumors and anticipate that the molecules disclosed can be used as starting points for future efforts toward compounds with improved drug-like properties.


Assuntos
Descoberta de Drogas , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Ácido Salicílico/química , Bibliotecas de Moléculas Pequenas/farmacologia , Sulfonamidas/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ligação Proteica , Conformação Proteica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Repetições WD40
5.
Cell Rep ; 26(11): 2916-2928.e13, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30865883

RESUMO

The chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of the "WIN site" of WDR5, a well-defined pocket that is amenable to small molecule inhibition. Various cancer contexts have been proposed to be targets for WIN site inhibitors, but a lack of understanding of WDR5 target genes and of the primary effects of WIN site inhibitors hampers their utility. Here, by the discovery of potent WIN site inhibitors, we demonstrate that the WIN site links WDR5 to chromatin at a small cohort of loci, including a specific subset of ribosome protein genes. WIN site inhibitors rapidly displace WDR5 from chromatin and decrease the expression of associated genes, causing translational inhibition, nucleolar stress, and p53 induction. Our studies define a mode by which WDR5 engages chromatin and forecast that WIN site blockade could have utility against multiple cancer types.


Assuntos
Cromatina/metabolismo , Inibidores Enzimáticos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Inibidores Enzimáticos/síntese química , Feminino , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/química , Masculino , Ligação Proteica/efeitos dos fármacos
6.
J Med Chem ; 61(13): 5623-5642, 2018 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-29889518

RESUMO

WDR5 is a chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage leukemia. Here, we describe the discovery of potent and selective WDR5-WIN-site inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified several chemically distinct hit series that bind to the WIN site within WDR5. Members of a 6,7-dihydro-5 H-pyrrolo[1,2- a]imidazole fragment class were expanded using a structure-based design approach to arrive at lead compounds with dissociation constants <10 nM and micromolar cellular activity against an AML-leukemia cell line. These compounds represent starting points for the discovery of clinically useful WDR5 inhibitors for the treatment of cancer.


Assuntos
Desenho de Fármacos , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/química , Imidazóis/química , Imidazóis/farmacologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Relação Estrutura-Atividade
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