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1.
Nat Chem Biol ; 13(7): 771-778, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28530711

RESUMO

Approved drugs are invaluable tools to study biochemical pathways, and further characterization of these compounds may lead to repurposing of single drugs or combinations. Here we describe a collection of 308 small molecules representing the diversity of structures and molecular targets of all FDA-approved chemical entities. The CeMM Library of Unique Drugs (CLOUD) covers prodrugs and active forms at pharmacologically relevant concentrations and is ideally suited for combinatorial studies. We screened pairwise combinations of CLOUD drugs for impairment of cancer cell viability and discovered a synergistic interaction between flutamide and phenprocoumon (PPC). The combination of these drugs modulates the stability of the androgen receptor (AR) and resensitizes AR-mutant prostate cancer cells to flutamide. Mechanistically, we show that the AR is a substrate for γ-carboxylation, a post-translational modification inhibited by PPC. Collectively, our data suggest that PPC could be repurposed to tackle resistance to antiandrogens in prostate cancer patients.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Receptores Androgênicos/metabolismo , Bibliotecas de Moléculas Pequenas/análise , Bibliotecas de Moléculas Pequenas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Flutamida/farmacologia , Humanos , Masculino , Estrutura Molecular , Femprocumona/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
2.
Pharmacol Res ; 107: 390-397, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26816086

RESUMO

Non-oncogene addiction exploits cancer vulnerabilities resulting from altered cellular signaling pathways in response to oncogenic mutations that are not directly druggable. In this perspective, we address recent findings showing how the SUMOylation cascade provides a synthetic lethal target in the context of different malignant transformations. Functional genomics screens have revealed that the activation of oncogenes such as NOTCH1, MYC or KRAS generates a cancer-specific dependency on SUMOylation. Pharmacological targeting of the SUMOylation cascade induces cancer cell death in these settings, suggesting potential therapeutic applications in oncology. However, the physicochemical properties of the few currently available SUMOylation inhibitors preclude clear-cut investigations and clinical testing. We therefore encourage the development of better chemical probes targeting this multifaceted post-translational modification. Such optimized molecules would enable proof of concept studies to evaluate the therapeutic potential of non-oncogene addiction to SUMO.


Assuntos
Neoplasias/metabolismo , Sumoilação , Animais , Humanos , Neoplasias/tratamento farmacológico
3.
RSC Med Chem ; 13(12): 1446-1459, 2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36545432

RESUMO

Small-molecule chemical probes are among the most important tools to study the function of proteins in cells and organisms. Regrettably, the use of weak and non-selective small molecules has generated an abundance of erroneous conclusions in the scientific literature. More recently, minimal criteria have been outlined for investigational compounds, encouraging the selection and use of high-quality chemical probes. Here, we briefly recall the milestones and key initiatives that have paved the way to this new era, illustrate examples of recent high-quality chemical probes and provide our perspective on future challenges and developments.

4.
Trends Pharmacol Sci ; 42(5): 313-315, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33771354

RESUMO

Casein kinase 2 (CK2) is highly expressed in cancer and has been considered a potential therapeutic target. Wells and colleagues developed and characterized the new CK2 inhibitor SGC-CK2-1. Unexpectedly, this potent and highly selective chemical probe does not show broad antiproliferative activity in cancer cells.


Assuntos
Caseína Quinase II , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases
5.
J Clin Invest ; 130(11): 5875-5892, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33016930

RESUMO

The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 - a component of the transcription elongation complex P-TEFb - bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma.


Assuntos
Adenosina/análogos & derivados , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Proteína Proto-Oncogênica N-Myc/biossíntese , Neuroblastoma/tratamento farmacológico , Temozolomida/farmacologia , Adenosina/farmacologia , Linhagem Celular Tumoral , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 9 Dependente de Ciclina/metabolismo , Elementos Facilitadores Genéticos , Humanos , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Fator B de Elongação Transcricional Positiva/genética , Fator B de Elongação Transcricional Positiva/metabolismo , Transcrição Gênica/efeitos dos fármacos
6.
Nat Commun ; 10(1): 5140, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31723137

RESUMO

Drug combinations provide effective treatments for diverse diseases, but also represent a major cause of adverse reactions. Currently there is no systematic understanding of how the complex cellular perturbations induced by different drugs influence each other. Here, we introduce a mathematical framework for classifying any interaction between perturbations with high-dimensional effects into 12 interaction types. We apply our framework to a large-scale imaging screen of cell morphology changes induced by diverse drugs and their combination, resulting in a perturbome network of 242 drugs and 1832 interactions. Our analysis of the chemical and biological features of the drugs reveals distinct molecular fingerprints for each interaction type. We find a direct link between drug similarities on the cell morphology level and the distance of their respective protein targets within the cellular interactome of molecular interactions. The interactome distance is also predictive for different types of drug interactions.


Assuntos
Células/metabolismo , Interações Medicamentosas , Mapeamento de Interação de Proteínas , Linhagem Celular Tumoral , Forma Celular , Humanos , Modelos Biológicos
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