The Experts below are selected from a list of 519 Experts worldwide ranked by ideXlab platform
S Picaud - One of the best experts on this subject based on the ideXlab platform.
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[1,2,4]Triazolo[4,3‑a]phthalazines: Inhibitors of Diverse
2016Co-Authors: O Fedorov, Martin Philpott, Hannah Lingard, Octovia P Monteiro, S Picaud, T Keates, I Felletar, Chris Wells, Sarah J. Martin, Brian D. MarsdenAbstract:ABSTRACT: Bromodomains are gaining increasing interest as drug targets. Commercially sourced and de novo synthesized substituted [1,2,4]triazolo[4,3-a]phthalazines are potent inhibitors of both the BET bromodomains such as BRD4 as well as bromodomains outside the BET family such as BRD9, CECR2, and CREBBP. This new series of compounds is the first example of submicromolar inhibitors of bromodomains outside the BET subfamily. Representative compounds are active in cells exhibiting potent cellular inhibition activity in a FRAP model of CREBBP and chromatin association. The compounds described are valuable starting points for discovery of selective bromodomain inhibitors and inhibitors with mixed bromodomain pharmacology. The rapidly expanding field of epigenetics can be broadly divided into two levels of processes: DNA methylation and histone modification. Various post-translational modification
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1 2 4 triazolo 4 3 a phthalazines inhibitors of diverse bromodomains
Journal of Medicinal Chemistry, 2014Co-Authors: O Fedorov, Martin Philpott, Hannah Lingard, Christopher Wells, Octovia P Monteiro, S Picaud, T Keates, Clarence Yapp, Sarah Martin, I FelletarAbstract:Bromodomains are gaining increasing interest as drug targets. Commercially sourced and de novo synthesized substituted [1,2,4]triazolo[4,3-a]phthalazines are potent inhibitors of both the BET bromodomains such as BRD4 as well as bromodomains outside the BET family such as BRD9, CECR2, and CREBBP. This new series of compounds is the first example of submicromolar inhibitors of bromodomains outside the BET subfamily. Representative compounds are active in cells exhibiting potent cellular inhibition activity in a FRAP model of CREBBP and chromatin association. The compounds described are valuable starting points for discovery of selective bromodomain inhibitors and inhibitors with mixed bromodomain pharmacology.
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discovery of novel small molecule inhibitors of brd4 using structure based virtual screening
Journal of Medicinal Chemistry, 2013Co-Authors: Lewis R Vidler, S Picaud, Sarah Martin, P Filippakopoulos, Michael Tomsett, Hannah Woodward, Nathan Brown, S Knapp, Swen HoelderAbstract:Bromodomains (BRDs) are epigenetic readers that recognize acetylated-lysine (KAc) on proteins and are implicated in a number of diseases. We describe a virtual screening approach to identify BRD inhibitors. Key elements of this approach are the extensive design and use of substructure queries to compile a set of commercially available compounds featuring novel putative KAc mimetics and docking this set for final compound selection. We describe the validation of this approach by applying it to the first BRD of BRD4. The selection and testing of 143 compounds lead to the discovery of six novel hits, including four unprecedented KAc mimetics. We solved the crystal structure of four hits, determined their binding mode, and improved their potency through synthesis and the purchase of derivatives. This work provides a validated virtual screening approach that is applicable to other BRDs and describes novel KAc mimetics that can be further explored to design more potent inhibitors.
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pfi 1 a highly selective protein interaction inhibitor targeting bet bromodomains
Cancer Research, 2013Co-Authors: S Picaud, O Fedorov, Martin Philpott, P Filippakopoulos, David Da Costa, Angeliki Thanasopoulou, Paul V Fish, P E Brennan, Mark E Bunnage, Dafydd R OwenAbstract:Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are transcriptional regulators required for efficient expression of several growth promoting and antiapoptotic genes as well as for cell-cycle progression. BET proteins are recruited on transcriptionally active chromatin via their two N-terminal bromodomains (BRD), a protein interaction module that specifically recognizes acetylated lysine residues in histones H3 and H4. Inhibition of the BET-histone interaction results in transcriptional downregulation of a number of oncogenes, providing a novel pharmacologic strategy for the treatment of cancer. Here, we present a potent and highly selective dihydroquinazoline-2-one inhibitor, PFI-1, which efficiently blocks the interaction of BET BRDs with acetylated histone tails. Cocrystal structures showed that PFI-1 acts as an acetyl-lysine (Kac) mimetic inhibitor efficiently occupying the Kac binding site in BRD4 and BRD2. PFI-1 has antiproliferative effects on leukemic cell lines and efficiently abrogates their clonogenic growth. Exposure of sensitive cell lines with PFI-1 results in G1 cell-cycle arrest, downregulation of MYC expression, as well as induction of apoptosis and induces differentiation of primary leukemic blasts. Intriguingly, cells exposed to PFI-1 showed significant downregulation of Aurora B kinase, thus attenuating phosphorylation of the Aurora substrate H3S10, providing an alternative strategy for the specific inhibition of this well-established oncology target.
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histone recognition and large scale structural analysis of the human bromodomain family
Cell, 2012Co-Authors: P Filippakopoulos, S Picaud, T Keates, I Felletar, Susanne Muller, Maria M Mangos, Jeanphilippe Lambert, Dalia Barsytelovejoy, Rudolf Volkmer, Tony PawsonAbstract:Bromodomains (BRDs) are protein interaction modules that specifically recognize e-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks. The 61 BRDs in the human genome cluster into eight families based on structure/sequence similarity. Here, we present 29 high-resolution crystal structures, covering all BRD families. Comprehensive crossfamily structural analysis identifies conserved and family-specific structural features that are necessary for specific acetylation-dependent substrate recognition. Screening of more than 30 representative BRDs against systematic histone-peptide arrays identifies new BRD substrates and reveals a strong influence of flanking posttranslational modifications, such as acetylation and phosphorylation, suggesting that BRDs recognize combinations of marks rather than singly acetylated sequences. We further uncovered a structural mechanism for the simultaneous binding and recognition of diverse diacetyl-containing peptides by BRD4. These data provide a foundation for structure-based drug design of specific inhibitors for this emerging target family.
I Felletar - One of the best experts on this subject based on the ideXlab platform.
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[1,2,4]Triazolo[4,3‑a]phthalazines: Inhibitors of Diverse
2016Co-Authors: O Fedorov, Martin Philpott, Hannah Lingard, Octovia P Monteiro, S Picaud, T Keates, I Felletar, Chris Wells, Sarah J. Martin, Brian D. MarsdenAbstract:ABSTRACT: Bromodomains are gaining increasing interest as drug targets. Commercially sourced and de novo synthesized substituted [1,2,4]triazolo[4,3-a]phthalazines are potent inhibitors of both the BET bromodomains such as BRD4 as well as bromodomains outside the BET family such as BRD9, CECR2, and CREBBP. This new series of compounds is the first example of submicromolar inhibitors of bromodomains outside the BET subfamily. Representative compounds are active in cells exhibiting potent cellular inhibition activity in a FRAP model of CREBBP and chromatin association. The compounds described are valuable starting points for discovery of selective bromodomain inhibitors and inhibitors with mixed bromodomain pharmacology. The rapidly expanding field of epigenetics can be broadly divided into two levels of processes: DNA methylation and histone modification. Various post-translational modification
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1 2 4 triazolo 4 3 a phthalazines inhibitors of diverse bromodomains
Journal of Medicinal Chemistry, 2014Co-Authors: O Fedorov, Martin Philpott, Hannah Lingard, Christopher Wells, Octovia P Monteiro, S Picaud, T Keates, Clarence Yapp, Sarah Martin, I FelletarAbstract:Bromodomains are gaining increasing interest as drug targets. Commercially sourced and de novo synthesized substituted [1,2,4]triazolo[4,3-a]phthalazines are potent inhibitors of both the BET bromodomains such as BRD4 as well as bromodomains outside the BET family such as BRD9, CECR2, and CREBBP. This new series of compounds is the first example of submicromolar inhibitors of bromodomains outside the BET subfamily. Representative compounds are active in cells exhibiting potent cellular inhibition activity in a FRAP model of CREBBP and chromatin association. The compounds described are valuable starting points for discovery of selective bromodomain inhibitors and inhibitors with mixed bromodomain pharmacology.
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histone recognition and large scale structural analysis of the human bromodomain family
Cell, 2012Co-Authors: P Filippakopoulos, S Picaud, T Keates, I Felletar, Susanne Muller, Maria M Mangos, Jeanphilippe Lambert, Dalia Barsytelovejoy, Rudolf Volkmer, Tony PawsonAbstract:Bromodomains (BRDs) are protein interaction modules that specifically recognize e-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks. The 61 BRDs in the human genome cluster into eight families based on structure/sequence similarity. Here, we present 29 high-resolution crystal structures, covering all BRD families. Comprehensive crossfamily structural analysis identifies conserved and family-specific structural features that are necessary for specific acetylation-dependent substrate recognition. Screening of more than 30 representative BRDs against systematic histone-peptide arrays identifies new BRD substrates and reveals a strong influence of flanking posttranslational modifications, such as acetylation and phosphorylation, suggesting that BRDs recognize combinations of marks rather than singly acetylated sequences. We further uncovered a structural mechanism for the simultaneous binding and recognition of diverse diacetyl-containing peptides by BRD4. These data provide a foundation for structure-based drug design of specific inhibitors for this emerging target family.
Steven J Husson - One of the best experts on this subject based on the ideXlab platform.
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the bet family of proteins targets moloney murine leukemia virus integration near transcription start sites
Cell Reports, 2013Co-Authors: Jan De Rijck, Christine De Kogel, Jonas Demeulemeester, Sofie Vets, Sara El Ashkar, Nirav Malani, Frederic D Bushman, Bart Landuyt, Steven J HussonAbstract:Summary A hallmark of retroviral replication is integration of the viral genome into host cell DNA. This characteristic makes retrovirus-based vectors attractive delivery vehicles for gene therapy. However, adverse events in gene therapeutic trials, caused by activation of proto-oncogenes due to murine leukemia virus (MLV)-derived vector integration, hamper their application. Here, we show that bromodomain and extraterminal (BET) proteins (BRD2, BRD3, and BRD4) and MLV integrase specifically interact and colocalize within the nucleus of the cell. Inhibition of the BET proteins' chromatin interaction via specific bromodomain inhibitors blocks MLV virus replication at the integration step. MLV integration site distribution parallels the chromatin binding profile of BET proteins, and expression of an artificial fusion protein of the BET integrase binding domain with the chromatin interaction domain of the lentiviral targeting factor LEDGF/p75 retargets MLV integration away from transcription start sites and into the body of actively transcribed genes, conforming to the HIV integration pattern. Together, these data validate BET proteins as MLV integration targeting factors.
O Fedorov - One of the best experts on this subject based on the ideXlab platform.
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[1,2,4]Triazolo[4,3‑a]phthalazines: Inhibitors of Diverse
2016Co-Authors: O Fedorov, Martin Philpott, Hannah Lingard, Octovia P Monteiro, S Picaud, T Keates, I Felletar, Chris Wells, Sarah J. Martin, Brian D. MarsdenAbstract:ABSTRACT: Bromodomains are gaining increasing interest as drug targets. Commercially sourced and de novo synthesized substituted [1,2,4]triazolo[4,3-a]phthalazines are potent inhibitors of both the BET bromodomains such as BRD4 as well as bromodomains outside the BET family such as BRD9, CECR2, and CREBBP. This new series of compounds is the first example of submicromolar inhibitors of bromodomains outside the BET subfamily. Representative compounds are active in cells exhibiting potent cellular inhibition activity in a FRAP model of CREBBP and chromatin association. The compounds described are valuable starting points for discovery of selective bromodomain inhibitors and inhibitors with mixed bromodomain pharmacology. The rapidly expanding field of epigenetics can be broadly divided into two levels of processes: DNA methylation and histone modification. Various post-translational modification
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lp99 discovery and synthesis of the first selective brd7 9 bromodomain inhibitor
Angewandte Chemie, 2015Co-Authors: Peter G K Clark, O Fedorov, Octovia P Monteiro, C Tallant, Lucas C C Vieira, Dean C Singleton, Catherine Rogers, James M Bennett, Roberta Baronio, Susanne MullerAbstract:The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure–activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.
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1 2 4 triazolo 4 3 a phthalazines inhibitors of diverse bromodomains
Journal of Medicinal Chemistry, 2014Co-Authors: O Fedorov, Martin Philpott, Hannah Lingard, Christopher Wells, Octovia P Monteiro, S Picaud, T Keates, Clarence Yapp, Sarah Martin, I FelletarAbstract:Bromodomains are gaining increasing interest as drug targets. Commercially sourced and de novo synthesized substituted [1,2,4]triazolo[4,3-a]phthalazines are potent inhibitors of both the BET bromodomains such as BRD4 as well as bromodomains outside the BET family such as BRD9, CECR2, and CREBBP. This new series of compounds is the first example of submicromolar inhibitors of bromodomains outside the BET subfamily. Representative compounds are active in cells exhibiting potent cellular inhibition activity in a FRAP model of CREBBP and chromatin association. The compounds described are valuable starting points for discovery of selective bromodomain inhibitors and inhibitors with mixed bromodomain pharmacology.
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pfi 1 a highly selective protein interaction inhibitor targeting bet bromodomains
Cancer Research, 2013Co-Authors: S Picaud, O Fedorov, Martin Philpott, P Filippakopoulos, David Da Costa, Angeliki Thanasopoulou, Paul V Fish, P E Brennan, Mark E Bunnage, Dafydd R OwenAbstract:Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are transcriptional regulators required for efficient expression of several growth promoting and antiapoptotic genes as well as for cell-cycle progression. BET proteins are recruited on transcriptionally active chromatin via their two N-terminal bromodomains (BRD), a protein interaction module that specifically recognizes acetylated lysine residues in histones H3 and H4. Inhibition of the BET-histone interaction results in transcriptional downregulation of a number of oncogenes, providing a novel pharmacologic strategy for the treatment of cancer. Here, we present a potent and highly selective dihydroquinazoline-2-one inhibitor, PFI-1, which efficiently blocks the interaction of BET BRDs with acetylated histone tails. Cocrystal structures showed that PFI-1 acts as an acetyl-lysine (Kac) mimetic inhibitor efficiently occupying the Kac binding site in BRD4 and BRD2. PFI-1 has antiproliferative effects on leukemic cell lines and efficiently abrogates their clonogenic growth. Exposure of sensitive cell lines with PFI-1 results in G1 cell-cycle arrest, downregulation of MYC expression, as well as induction of apoptosis and induces differentiation of primary leukemic blasts. Intriguingly, cells exposed to PFI-1 showed significant downregulation of Aurora B kinase, thus attenuating phosphorylation of the Aurora substrate H3S10, providing an alternative strategy for the specific inhibition of this well-established oncology target.
Fabian V Filipp - One of the best experts on this subject based on the ideXlab platform.
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bromodomain and extra terminal domain bet proteins regulate melanocyte differentiation
Epigenetics & Chromatin, 2020Co-Authors: Archit Trivedi, Aanchal Mehrotra, Caitlin E Baum, Brandon Lewis, Tupa Basuroy, Thomas M Blomquist, Robert J Trumbly, Fabian V FilippAbstract:Pharmacologic inhibition of bromodomain and extra-terminal (BET) proteins is currently being explored as a new therapeutic approach in cancer. Some studies have also implicated BET proteins as regulators of cell identity and differentiation through their interactions with lineage-specific factors. However, the role of BET proteins has not yet been investigated in melanocyte differentiation. Melanocyte inducing transcription factor (MITF) is the master regulator of melanocyte differentiation, essential for pigmentation and melanocyte survival. In this study, we tested the hypothesis that BET proteins regulate melanocyte differentiation through interactions with MITF. Here we show that chemical inhibition of BET proteins prevents differentiation of unpigmented melanoblasts into pigmented melanocytes and results in de-pigmentation of differentiated melanocytes. BET inhibition also slowed cell growth, without causing cell death, increasing the number of cells in G1. Transcriptional profiling revealed that BET inhibition resulted in decreased expression of pigment-specific genes, including many MITF targets. The expression of pigment-specific genes was also down-regulated in melanoma cells, but to a lesser extent. We found that RNAi depletion of the BET family members, bromodomain-containing protein 4 (BRD4) and bromodomain-containing protein 2 (BRD2) inhibited expression of two melanin synthesis enzymes, TYR and TYRP1. Both BRD4 and BRD2 were detected on melanocyte promoters surrounding MITF-binding sites, were associated with open chromatin structure, and promoted MITF binding to these sites. Furthermore, BRD4 and BRD2 physically interacted with MITF. These findings indicate a requirement for BET proteins in the regulation of pigmentation and melanocyte differentiation. We identified changes in pigmentation specific gene expression that occur upon BET inhibition in melanoblasts, melanocytes, and melanoma cells.