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1.
Nature ; 526(7572): 273-276, 2015 Oct 08.
Article in English | MEDLINE | ID: mdl-26416749

ABSTRACT

Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes. BRD4 and CDK7 are positive regulators of SE-mediated transcription. By contrast, negative regulators of SE-associated genes have not been well described. Here we show that the Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We report that the natural product cortistatin A (CA) selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and in vivo, and disproportionately induces upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the transcription factors CEBPA, IRF8, IRF1 and ETV6 (refs 6-8). The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has anti-leukaemic activity. Individually increasing or decreasing the expression of these transcription factors suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to the dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types, and can be pharmacologically targeted as a therapeutic approach to AML.


Subject(s)
Cyclin-Dependent Kinase 8/antagonists & inhibitors , Cyclin-Dependent Kinases/antagonists & inhibitors , Enhancer Elements, Genetic/genetics , Gene Expression Regulation, Neoplastic/genetics , Genes, Neoplasm/genetics , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/genetics , Animals , Cell Cycle Proteins , Cell Division/drug effects , Cell Line, Tumor , Cell Lineage/drug effects , Cell Lineage/genetics , Cyclin-Dependent Kinase 8/metabolism , Cyclin-Dependent Kinases/metabolism , Disease Progression , Down-Regulation/drug effects , Down-Regulation/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Genes, Tumor Suppressor/drug effects , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Male , Mice , Mice, Inbred Strains , Mice, SCID , Nuclear Proteins/antagonists & inhibitors , Polycyclic Compounds/pharmacology , Transcription Factors/antagonists & inhibitors , Transcription Factors/biosynthesis , Transcription Factors/genetics , Up-Regulation/drug effects , Up-Regulation/genetics
2.
Bioorg Med Chem Lett ; 23(13): 3942-6, 2013 Jul 01.
Article in English | MEDLINE | ID: mdl-23683596

ABSTRACT

A series of novel 2-phenylindole analogs were synthesized and evaluated for activity in subgenomic HCV replicon inhibition assays. Several compounds containing small alkyl sulfonamides on the phenyl ring exhibiting submicromolar EC50 values against the genotype 1b replicon were identified. Among these, compound 25d potently inhibited the 1b replicon (EC50=0.17 µM) with 147-fold selectivity with respect to cytotoxicity. Compound 25d was stable in the presence of human liver microsomes and had a good pharmacokinetic profile in rats with an IV half-life of 4.3h and oral bioavailability (F) of 58%.


Subject(s)
Antiviral Agents/pharmacology , Drug Discovery , Hepacivirus/drug effects , Indoles/pharmacology , Microsomes, Liver/drug effects , Sulfonamides/pharmacology , Virus Replication/drug effects , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/chemistry , Biological Availability , Dose-Response Relationship, Drug , Humans , Indoles/chemical synthesis , Indoles/chemistry , Microbial Sensitivity Tests , Molecular Structure , Rats , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry
3.
J Nat Prod ; 74(4): 567-73, 2011 Apr 25.
Article in English | MEDLINE | ID: mdl-21348461

ABSTRACT

The natural product austocystin D was identified as a potent cytotoxic agent with in vivo antitumor activity and selectivity for cells expressing the multidrug resistance transporter MDR1. We sought to elucidate the mechanism of austocystin D's selective cytotoxic activity. Here we show that the selective cytotoxic action of austocystin D arises from its selective activation by cytochrome P450 (CYP) enzymes in specific cancer cell lines, leading to induction of DNA damage in cells and in vitro. The potency and selectivity of austocystin D is lost upon inhibition of CYP activation and does not require MDR1 expression or activity. Furthermore, the pattern of cytotoxicity of austocystin D was distinct from doxorubicin and etoposide and unlike aflatoxin B(1), a compound that resembles austocystin D and is also activated by CYP enzymes to induce DNA damage. Theses results suggest that austocystin D may be of clinical benefit for targeting or overcoming chemoresistance.


Subject(s)
Aflatoxin B1/pharmacology , Aflatoxins/isolation & purification , Aflatoxins/pharmacology , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Aspergillus/chemistry , Cytochrome P-450 Enzyme System/drug effects , Drug Resistance, Multiple/drug effects , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP-Binding Cassette Transporters/drug effects , Aflatoxins/chemistry , Antineoplastic Agents/chemistry , Cytochrome P-450 Enzyme System/metabolism , DNA Damage/drug effects , DNA Damage/physiology , Drug Screening Assays, Antitumor , Humans , Molecular Structure
4.
J Am Chem Soc ; 127(15): 5596-603, 2005 Apr 20.
Article in English | MEDLINE | ID: mdl-15826198

ABSTRACT

An efficient, highly convergent stereocontrolled synthesis of (+)-discodermolide has been achieved with 2.1% overall yield (27 steps longest linear sequence). The absolute stereochemistry of the C1-C6 (12), C7-C14 (13), and C15-C24 (11) subunits was introduced using asymmetric crotylation methodology. Key elements of the synthesis include the use of hydrozirconation-cross-coupling methodology for the construction of C13-C14 (Z)-olefin, acetate aldol reaction to construct the C6-C7 bond and install the C7 stereocenter with high levels of 1,5-anti stereoinduction, and the use of palladium-mediated sp(2)-sp(3) cross-coupling reaction to join the advanced fragments, which assembled the carbon framework of discodermolide.


Subject(s)
Alkanes/chemical synthesis , Carbamates/chemical synthesis , Lactones/chemical synthesis , Silanes/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Porifera/chemistry , Pyrones , Stereoisomerism
5.
Org Lett ; 4(14): 2397-400, 2002 Jul 11.
Article in English | MEDLINE | ID: mdl-12098256

ABSTRACT

[structure: see text] A convergent and stereoselective assembly of the C1-C14 subunit of marine natural product (+)-discodermolide has been completed. The approach employs chiral allylsilane bond construction methodology to establish four of the eight stereogenic centers. Key fragment coupling is achieved via an efficient stereoselective acetate aldol reaction between C1-C6 and C7-C14 subunits.


Subject(s)
Alkanes , Antineoplastic Agents/chemical synthesis , Carbamates , Lactones/chemical synthesis , Porifera/chemistry , Animals , Indicators and Reagents , Pyrones , Stereoisomerism
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