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1.
Nucleic Acids Res ; 49(D1): D1074-D1082, 2021 01 08.
Article in English | MEDLINE | ID: mdl-33219674

ABSTRACT

canSAR (http://cansar.icr.ac.uk) is the largest, public, freely available, integrative translational research and drug discovery knowledgebase for oncology. canSAR integrates vast multidisciplinary data from across genomic, protein, pharmacological, drug and chemical data with structural biology, protein networks and more. It also provides unique data, curation and annotation and crucially, AI-informed target assessment for drug discovery. canSAR is widely used internationally by academia and industry. Here we describe significant developments and enhancements to the data, web interface and infrastructure of canSAR in the form of the new implementation of the system: canSARblack. We demonstrate new functionality in aiding translation hypothesis generation and experimental design, and show how canSAR can be adapted and utilised outside oncology.


Subject(s)
Computational Biology/methods , Databases, Genetic , Drug Discovery/methods , Knowledge Bases , Neoplasms/genetics , Translational Research, Biomedical/methods , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Data Mining/methods , Genomics/methods , Humans , Internet , Medical Oncology/methods , Molecular Structure , Neoplasms/metabolism , Proteomics/methods , User-Computer Interface
2.
Angew Chem Int Ed Engl ; 55(38): 11382-6, 2016 09 12.
Article in English | MEDLINE | ID: mdl-27530368

ABSTRACT

ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of that target class. Starting from a potent lead, permeability and selectivity were improved through a dual approach: 1) using CF2 as a sulfone bio-isostere to exploit the unique properties of fluorine, and 2) using 1,3-interactions to control the conformation of a piperidine ring. This resulted in the first reported low-nanomolar, selective and cell permeable chemical probe for ATAD2.

3.
Curr Opin Chem Biol ; 33: 151-9, 2016 08.
Article in English | MEDLINE | ID: mdl-27371875

ABSTRACT

Within the last decade we have witnessed significant progress in the field of chromatin methylation, ranging from the discovery that chromatin methylation is reversible, to the identification of two classes of oxidative chromatin demethylases. Multiple genetic and cellular studies emphasize the role of members of the amine oxidase and 2-oxoglutarate oxygenase enzyme families involved in methyl-lysine in physiology and disease. Advances in understanding of the underlying biochemistry have resulted in development of first series of clinical inhibitors and tool compounds which continue to resolve and help understand the complex relationships between chromatin modification, control of gene expression and metabolic states.


Subject(s)
Histone Demethylases/metabolism , Catalysis , Clinical Trials as Topic , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Epigenesis, Genetic , Genomics , Histone Demethylases/antagonists & inhibitors , Histones/chemistry , Histones/metabolism , Humans , Lysine/metabolism , Methylation
4.
J Med Chem ; 59(4): 1425-39, 2016 Feb 25.
Article in English | MEDLINE | ID: mdl-25856009

ABSTRACT

Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain "reader" modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition.


Subject(s)
Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Transcription Factors/antagonists & inhibitors , Transcription Factors/metabolism , Amino Acid Sequence , Binding Sites , Cell Line , Crystallography, X-Ray , Drug Discovery , Humans , Models, Molecular , Molecular Docking Simulation , Transcription Factors/chemistry
5.
Cancer Res ; 75(23): 5106-5119, 2015 Dec 01.
Article in English | MEDLINE | ID: mdl-26552700

ABSTRACT

The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and are key regulators of cell growth. Therefore, efforts to generate inhibitors of CBP/p300 are of clinical value. We developed a specific and potent acetyl-lysine competitive protein-protein interaction inhibitor, I-CBP112, that targets the CBP/p300 bromodomains. Exposure of human and mouse leukemic cell lines to I-CBP112 resulted in substantially impaired colony formation and induced cellular differentiation without significant cytotoxicity. I-CBP112 significantly reduced the leukemia-initiating potential of MLL-AF9(+) acute myeloid leukemia cells in a dose-dependent manner in vitro and in vivo. Interestingly, I-CBP112 increased the cytotoxic activity of BET bromodomain inhibitor JQ1 as well as doxorubicin. Collectively, we report the development and preclinical evaluation of a novel, potent inhibitor targeting CBP/p300 bromodomains that impairs aberrant self-renewal of leukemic cells. The synergistic effects of I-CBP112 and current standard therapy (doxorubicin) as well as emerging treatment strategies (BET inhibition) provide new opportunities for combinatorial treatment of leukemia and potentially other cancers.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Enzyme Inhibitors/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Oxazepines/pharmacology , p300-CBP Transcription Factors/antagonists & inhibitors , Amino Acid Sequence , Animals , Cell Line, Tumor , Doxorubicin/administration & dosage , Doxorubicin/pharmacology , Drug Synergism , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Humans , Leukemia, Myeloid, Acute/enzymology , Mice , Models, Molecular , Molecular Sequence Data , Oxazepines/administration & dosage , Oxazepines/chemistry , Protein Structure, Tertiary , Xenograft Model Antitumor Assays , p300-CBP Transcription Factors/chemistry
6.
Chem Sci ; 4(8): 3110-3117, 2013 Aug 01.
Article in English | MEDLINE | ID: mdl-26682036

ABSTRACT

2-Oxoglutarate and iron dependent oxygenases are therapeutic targets for human diseases. Using a representative 2OG oxygenase panel, we compare the inhibitory activities of 5-carboxy-8-hydroxyquinoline (IOX1) and 4-carboxy-8-hydroxyquinoline (4C8HQ) with that of two other commonly used 2OG oxygenase inhibitors, N-oxalylglycine (NOG) and 2,4-pyridinedicarboxylic acid (2,4-PDCA). The results reveal that IOX1 has a broad spectrum of activity, as demonstrated by the inhibition of transcription factor hydroxylases, representatives of all 2OG dependent histone demethylase subfamilies, nucleic acid demethylases and γ-butyrobetaine hydroxylase. Cellular assays show that, unlike NOG and 2,4-PDCA, IOX1 is active against both cytosolic and nuclear 2OG oxygenases without ester derivatisation. Unexpectedly, crystallographic studies on these oxygenases demonstrate that IOX1, but not 4C8HQ, can cause translocation of the active site metal, revealing a rare example of protein ligand-induced metal movement.

7.
J Med Chem ; 55(14): 6639-43, 2012 Jul 26.
Article in English | MEDLINE | ID: mdl-22724510

ABSTRACT

The JmjC oxygenases catalyze the N-demethylation of N(ε)-methyl lysine residues in histones and are current therapeutic targets. A set of human 2-oxoglutarate analogues were screened using a unified assay platform for JmjC demethylases and related oxygenases. Results led to the finding that daminozide (N-(dimethylamino)succinamic acid, 160 Da), a plant growth regulator, selectively inhibits the KDM2/7 JmjC subfamily. Kinetic and crystallographic studies reveal that daminozide chelates the active site metal via its hydrazide carbonyl and dimethylamino groups.


Subject(s)
Enzyme Inhibitors/pharmacology , Jumonji Domain-Containing Histone Demethylases/antagonists & inhibitors , Plant Growth Regulators/pharmacology , Succinates/pharmacology , Humans , Inhibitory Concentration 50 , Jumonji Domain-Containing Histone Demethylases/chemistry , Jumonji Domain-Containing Histone Demethylases/metabolism , Models, Molecular , Protein Conformation , Substrate Specificity
8.
Nat Commun ; 3: 662, 2012 Feb 07.
Article in English | MEDLINE | ID: mdl-22314358

ABSTRACT

Beclin 1 is a core component of the Class III Phosphatidylinositol 3-Kinase VPS34 complex. The coiled coil domain of Beclin 1 serves as an interaction platform for assembly of distinct Atg14L- and UVRAG-containing complexes to modulate VPS34 activity. Here we report the crystal structure of the coiled coil domain that forms an antiparallel dimer and is rendered metastable by a series of 'imperfect' a-d' pairings at its coiled coil interface. Atg14L and UVRAG promote the transition of metastable homodimeric Beclin 1 to heterodimeric Beclin1-Atg14L/UVRAG assembly. Beclin 1 mutants with their 'imperfect' a-d' pairings modified to enhance self-interaction, show distinctively altered interactions with Atg14L or UVRAG. These results suggest that specific utilization of the dimer interface and modulation of the homodimer-heterodimer transition by Beclin 1-interacting partners may underlie the molecular mechanism that controls the formation of various Beclin1-VPS34 subcomplexes to exert their effect on an array of VPS34-related activities, including autophagy.


Subject(s)
Adaptor Proteins, Vesicular Transport/chemistry , Apoptosis Regulatory Proteins/metabolism , Membrane Proteins/metabolism , Tumor Suppressor Proteins/chemistry , Amino Acid Motifs , Amino Acid Sequence , Autophagy , Autophagy-Related Proteins , Beclin-1 , Class III Phosphatidylinositol 3-Kinases/chemistry , Crystallography, X-Ray/methods , Dimerization , HEK293 Cells , Humans , Models, Molecular , Molecular Conformation , Molecular Sequence Data , Mutation , Protein Structure, Tertiary , Sequence Homology, Amino Acid , Static Electricity , Temperature
10.
J Am Chem Soc ; 133(24): 9451-6, 2011 Jun 22.
Article in English | MEDLINE | ID: mdl-21585201

ABSTRACT

Histone methylations are important chromatin marks that regulate gene expression, genomic stability, DNA repair, and genomic imprinting. Histone demethylases are the most recent family of histone-modifying enzymes discovered. Here, we report the characterization of a small-molecule inhibitor of Jumonji C domain-containing histone demethylases. The inhibitor derives from a structure-based design and preferentially inhibits the subfamily of trimethyl lysine demethylases. Its methyl ester prodrug, methylstat, selectively inhibits Jumonji C domain-containing his-tone demethylases in cells and may be a useful small-molecule probe of chromatin and its role in epigenetics.


Subject(s)
Enzyme Inhibitors/pharmacology , Jumonji Domain-Containing Histone Demethylases/antagonists & inhibitors , Cell Line, Tumor , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Esters , Histone Demethylases/antagonists & inhibitors , Histone Demethylases/metabolism , Humans , Inhibitory Concentration 50 , Jumonji Domain-Containing Histone Demethylases/chemistry , Jumonji Domain-Containing Histone Demethylases/metabolism , Muscle Development/drug effects , Nuclear Proteins/antagonists & inhibitors , Nuclear Proteins/metabolism , Prodrugs/metabolism , Prodrugs/pharmacology , Substrate Specificity
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