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Nature Oct 2017The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory...
The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have also been implicated in human pathological conditions (including cancer). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products, bi-substrate analogues and the widely used small molecule C646, lack potency or selectivity. Here, we describe A-485, a potent, selective and drug-like catalytic inhibitor of p300 and CBP. We present a high resolution (1.95 Å) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 competes with acetyl coenzyme A (acetyl-CoA). A-485 selectively inhibited proliferation in lineage-specific tumour types, including several haematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibited tumour growth in a castration-resistant xenograft model. These results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases.
Topics: Acetyl Coenzyme A; Animals; Antineoplastic Agents; Binding, Competitive; Biocatalysis; Catalytic Domain; Cell Line, Tumor; Cell Lineage; Cell Proliferation; Crystallography, X-Ray; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Hematologic Neoplasms; Heterocyclic Compounds, 4 or More Rings; Histone Acetyltransferases; Humans; Male; Mice; Mice, SCID; Models, Molecular; Neoplasms; Prostatic Neoplasms, Castration-Resistant; Protein Conformation; Receptors, Androgen; Xenograft Model Antitumor Assays; p300-CBP Transcription Factors
PubMed: 28953875
DOI: 10.1038/nature24028 -
Nature Chemical Biology May 2017Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional...
Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4. Structure-based-designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation.
Topics: Amino Acid Sequence; Cell Cycle Proteins; Crystallography, X-Ray; Dipeptides; Elongin; Heterocyclic Compounds, 3-Ring; Humans; Models, Molecular; Multiprotein Complexes; Nuclear Proteins; Protein Binding; Protein Conformation; Proteolysis; Small Molecule Libraries; Structure-Activity Relationship; Thermodynamics; Transcription Factors; Ubiquitin-Protein Ligases; Von Hippel-Lindau Tumor Suppressor Protein
PubMed: 28288108
DOI: 10.1038/nchembio.2329 -
Cell Jun 2018The acetyltransferases CBP and p300 are multifunctional transcriptional co-activators. Here, we combined quantitative proteomics with CBP/p300-specific catalytic...
The acetyltransferases CBP and p300 are multifunctional transcriptional co-activators. Here, we combined quantitative proteomics with CBP/p300-specific catalytic inhibitors, bromodomain inhibitor, and gene knockout to reveal a comprehensive map of regulated acetylation sites and their dynamic turnover rates. CBP/p300 acetylates thousands of sites, including signature histone sites and a multitude of sites on signaling effectors and enhancer-associated transcriptional regulators. Time-resolved acetylome analyses identified a subset of CBP/p300-regulated sites with very rapid (<30 min) acetylation turnover, revealing a dynamic balance between acetylation and deacetylation. Quantification of acetylation, mRNA, and protein abundance after CBP/p300 inhibition reveals a kinetically competent network of gene expression that strictly depends on CBP/p300-catalyzed rapid acetylation. Collectively, our in-depth acetylome analyses reveal systems attributes of CBP/p300 targets, and the resource dataset provides a framework for investigating CBP/p300 functions and for understanding the impact of small-molecule inhibitors targeting its catalytic and bromodomain activities.
Topics: Acetylation; Acetyltransferases; Animals; Cell Line; Gene Knockout Techniques; Half-Life; Heterocyclic Compounds, 4 or More Rings; Histones; Humans; Isotope Labeling; Kinetics; Mass Spectrometry; Mice; Peptides; Receptors, Aryl Hydrocarbon; Recombinant Proteins; Signal Transduction; Small Molecule Libraries; Transcriptome; p300-CBP Transcription Factors
PubMed: 29804834
DOI: 10.1016/j.cell.2018.04.033 -
Cancer Cell May 2019The mitochondrial caseinolytic protease P (ClpP) plays a central role in mitochondrial protein quality control by degrading misfolded proteins. Using genetic and...
The mitochondrial caseinolytic protease P (ClpP) plays a central role in mitochondrial protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the protease selectively kills cancer cells, independently of p53 status, by selective degradation of its respiratory chain protein substrates and disrupts mitochondrial structure and function, while it does not affect non-malignant cells. We identified imipridones as potent activators of ClpP. Through biochemical studies and crystallography, we show that imipridones bind ClpP non-covalently and induce proteolysis by diverse structural changes. Imipridones are presently in clinical trials. Our findings suggest a general concept of inducing cancer cell lethality through activation of mitochondrial proteolysis.
Topics: Animals; Cell Line, Tumor; Cell Survival; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Endopeptidase Clp; Female; HCT116 Cells; HEK293 Cells; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Leukemia, Myeloid, Acute; Mice; Mitochondria; Models, Molecular; Point Mutation; Protein Conformation; Proteolysis; Pyridines; Pyrimidines; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays
PubMed: 31056398
DOI: 10.1016/j.ccell.2019.03.014 -
ACS Chemical Biology Aug 2015The Bromo- and Extra-Terminal (BET) proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation, epigenetics, and cancer and are the targets of...
The Bromo- and Extra-Terminal (BET) proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation, epigenetics, and cancer and are the targets of pan-BET selective bromodomain inhibitor JQ1. However, the lack of intra-BET selectivity limits the scope of current inhibitors as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We designed Proteolysis Targeted Chimeras (PROTACs) that tether JQ1 to a ligand for the E3 ubiquitin ligase VHL, aimed at triggering the intracellular destruction of BET proteins. Compound MZ1 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 over BRD2 and BRD3. The activity of MZ1 is dependent on binding to VHL but is achieved at a sufficiently low concentration not to induce stabilization of HIF-1α. Gene expression profiles of selected cancer-related genes responsive to JQ1 reveal distinct and more limited transcriptional responses induced by MZ1, consistent with selective suppression of BRD4. Our discovery opens up new opportunities to elucidate the cellular phenotypes and therapeutic implications associated with selective targeting of BRD4.
Topics: Cell Cycle Proteins; Dipeptides; Drug Design; Gene Expression Regulation, Neoplastic; HeLa Cells; Heterocyclic Compounds, 3-Ring; Humans; Neoplasms; Nuclear Proteins; Proteolysis; Small Molecule Libraries; Transcription Factors; Ubiquitin-Protein Ligases; Von Hippel-Lindau Tumor Suppressor Protein
PubMed: 26035625
DOI: 10.1021/acschembio.5b00216 -
Chemistry & Biology Jun 2015BRD4, a bromodomain and extraterminal domain (BET) family member, is an attractive target in multiple pathological settings, particularly cancer. While BRD4 inhibitors...
BRD4, a bromodomain and extraterminal domain (BET) family member, is an attractive target in multiple pathological settings, particularly cancer. While BRD4 inhibitors have shown some promise in MYC-driven malignancies such as Burkitt's lymphoma (BL), we show that BRD4 inhibitors lead to robust BRD4 protein accumulation, which may account for their limited suppression of MYC expression, modest antiproliferative activity, and lack of apoptotic induction. To address these limitations we designed ARV-825, a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation of BRD4 in all BL cell lines tested. Consequently, ARV-825 more effectively suppresses c-MYC levels and downstream signaling than small-molecule BRD4 inhibitors, resulting in more effective cell proliferation inhibition and apoptosis induction in BL. Our findings provide strong evidence that cereblon-based PROTACs provide a better and more efficient strategy in targeting BRD4 than traditional small-molecule inhibitors.
Topics: Acetanilides; Adaptor Proteins, Signal Transducing; Apoptosis; Azepines; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Heterocyclic Compounds, 3-Ring; Humans; Nuclear Proteins; Peptide Hydrolases; Proto-Oncogene Proteins c-myc; Signal Transduction; Thalidomide; Transcription Factors; Triazoles; Ubiquitin-Protein Ligases
PubMed: 26051217
DOI: 10.1016/j.chembiol.2015.05.009 -
Applied Microbiology and Biotechnology May 2022The 5-membered oxadiazole and thiadiazole scaffolds are the most privileged and well-known heterocycles, being a common and essential feature of a variety of natural... (Review)
Review
The 5-membered oxadiazole and thiadiazole scaffolds are the most privileged and well-known heterocycles, being a common and essential feature of a variety of natural products and medicinal agents. These scaffolds take up the center position and are the core structural components of numerous drugs that belong to different categories. These include antimicrobial, anti-tubercular, anti-inflammatory, analgesic, antiepileptic, antiviral, and anticancer agents. In this review, we mostly talk about the isomers 1,2,4-oxadiazole and 1,3,4-thiadiazole because they have important pharmacological properties. This is partly because they are chemical and heat resistant, unlike other isomers, and they can be used as bio-isosteric replacements in drug design. We are reviewing the structural modifications of different oxadiazole and thiadiazole derivatives, more specifically, the anti-tubercular and anticancer pharmacological activities reported over the last 5 years, as we have undertaken this as a core area of research. This review article desires to do a thorough study and analysis of the recent progress made in the important biological isomers 1,2,4-oxadiazole and 1,3,4-thiadiazol. This will be a great place to start for future research. KEY POINTS: • Five-membered heterocyclic compound chemistry and biological activity recent survey. • Synthesis and pharmacological evolution of 1,2,4-oxadiazole and 1,3,4-thiadiazole are discussed in detail. • The value and significance of heterocyclic compounds in the field of drug designing are highlighted.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antineoplastic Agents; Oxadiazoles; Thiadiazoles
PubMed: 35562490
DOI: 10.1007/s00253-022-11969-0 -
Antibiotics (Basel, Switzerland) Dec 2022Heterocyclic compounds are considered as one of the major and most diverse family of organic compounds. Nowadays, the demand for these compounds is increasing day-by-day... (Review)
Review
Heterocyclic compounds are considered as one of the major and most diverse family of organic compounds. Nowadays, the demand for these compounds is increasing day-by-day due to their enormous synthetic and biological applications. These heterocyclic compounds have unique antibacterial activity against various Gram-positive and Gram-negative bacterial strains. This review covers the antibacterial activity of different heterocyclic compounds with nitrogen moiety. Some of the derivatives of these compounds show excellent antibacterial activity, while others show reasonable activity against bacterial strains. This review paper aims to bring and discuss the detailed information on the antibacterial activity of various nitrogen-based heterocyclic compounds. It will be helpful for the future evolution of diseases to synthesize new and effective drug molecules.
PubMed: 36551407
DOI: 10.3390/antibiotics11121750 -
Molecular Diversity Oct 2022The chemistry of nitrogen-containing heterocyclic compound pyrrole and pyrrolidine has been a versatile field of study for a long time for its diverse biological and... (Review)
Review
The chemistry of nitrogen-containing heterocyclic compound pyrrole and pyrrolidine has been a versatile field of study for a long time for its diverse biological and medicinal importance. Biomolecules such as chlorophyll, hemoglobin, myoglobin, and cytochrome are naturally occurring metal complexes of pyrrole. These metal complexes play a vital role in a living system like photosynthesis, oxygen carrier, as well storage, and redox cycling reactions. Apart from this, many medicinal drugs are derived from either pyrrole, pyrrolidine, or by its fused analogs. This review mainly focuses on the therapeutic potential of pyrrole, pyrrolidine, and its fused analogs, more specifically anticancer, anti-inflammatory, antiviral, and antituberculosis. Further, this review summarizes more recent reports on the pyrrole, pyrrolidine analogs, and their biological potential.
Topics: Anti-Inflammatory Agents; Antiviral Agents; Chlorophyll; Coordination Complexes; Cytochromes; Heterocyclic Compounds; Myoglobin; Nitrogen; Oxygen; Pyrroles; Pyrrolidines
PubMed: 35079946
DOI: 10.1007/s11030-022-10387-8 -
Marine Drugs Feb 2015In 1985 the first lamellarins were isolated from a small oceanic sea snail. Today, more than 50 lamellarins have been inventoried and numerous derivatives synthesized... (Review)
Review
In 1985 the first lamellarins were isolated from a small oceanic sea snail. Today, more than 50 lamellarins have been inventoried and numerous derivatives synthesized and tested as antiviral or anticancer agents. The lead compound in the family is lamellarin D, characterized as a potent inhibitor of both nuclear and mitochondrial topoisomerase I but also capable of directly interfering with mitochondria to trigger cancer cell death. The pharmacology and chemistry of lamellarins are discussed here and the mechanistic portrait of lamellarin D is detailed. Lamellarins frequently serve as a starting point in the design of anticancer compounds. Extensive efforts have been devoted to create novel structures as well as to improve synthetic methods, leading to lamellarins and related pyrrole-derived marine alkaloids.
Topics: Animals; Antineoplastic Agents; Cell Death; Coumarins; Drug Design; Heterocyclic Compounds, 4 or More Rings; Humans; Isoquinolines; Mitochondria; Mollusca; Neoplasms; Structure-Activity Relationship
PubMed: 25706633
DOI: 10.3390/md13031105