Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia

Picaud, S.; Leonards, Katharina; Lambert, Jean-Philippe; Dovey, Oliver M.; Wells, Christopher; Fedorov, Oleg; Monteiro, Octovia; Fujisawa, Takao; Wang, Chenyi; Lingard, Hannah; Tallant, C.; Nikbin, Nikzad; Guetzoyan, Lucie; Ingham, Richard J.; Ley, Steven V.; Brennan, P.E.; Müller, Susanne; Samsonova, Anastasia; Gingras, Anne‐Claude; Schwaller, Juerg; Vassiliou, George S.; Knapp, Stefan; Filippakopoulos, P.

doi:10.1126/sciadv.1600760

Cited by 101 publications

(107 citation statements)

References 65 publications

(92 reference statements)

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“…The broad‐spectrum bromodomain inhibitor bromosporine is, in contrast to specific BET bromodomain inhibitors such as (+)‐JQ1, less well studied in leukemia . Interestingly, however, it was demonstrated in leukemia cell lines that upon nonselective inhibition by bromosporine, the transcriptional effects were primarily due to inhibition of BET proteins, and not non‐BET bromodomain proteins . Treatment with LMK235, NSC3852, and bromosporine significantly inhibited leukemic cell survival in pediatric AML cell lines and primary patient cells, whereas we observed differential effects on the differentiation and viability of normal myeloid cells.…”

Section: Discussioncontrasting

confidence: 59%

Epigenetic drug screen identifies the histone deacetylase inhibitor NSC3852 as a potential novel drug for the treatment of pediatric acute myeloid leukemia

Wiggers

Govers

Lelieveld

et al. 2019

Pediatric Blood & Cancer

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Background Acute myeloid leukemia (AML) is a heterogeneous disease regarding morphology, immunophenotyping, genetic abnormalities, and clinical behavior. The overall survival rate of pediatric AML is 60% to 70%, and has not significantly improved over the past two decades. Children with Down syndrome (DS) are at risk of developing acute megakaryoblastic leukemia (AMKL), which can be preceded by a transient myeloproliferative disorder during the neonatal period. Intensification of current treatment protocols is not feasible due to already high treatment‐related morbidity and mortality. Instead, more targeted therapies with less severe side effects are highly needed. Procedure To identify potential novel therapeutic targets for myeloid disorders in children, including DS‐AMKL and non‐DS‐AML, we performed an unbiased compound screen of 80 small molecules targeting epigenetic regulators in three pediatric AML cell lines that are representative for different subtypes of pediatric AML. Three candidate compounds were validated and further evaluated in normal myeloid precursor cells during neutrophil differentiation and in (pre‐)leukemic pediatric patient cells. Results Candidate drugs LMK235, NSC3852, and bromosporine were effective in all tested pediatric AML cell lines with antiproliferative, proapoptotic, and differentiation effects. Out of these three compounds, the pan‐histone deacetylase inhibitor NSC3852 specifically induced growth arrest and apoptosis in pediatric AML cells, without disrupting normal neutrophil differentiation. Conclusion NSC3852 is a potential candidate drug for further preclinical testing in pediatric AML and DS‐AMKL.

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Section: Discussioncontrasting

confidence: 59%

Epigenetic drug screen identifies the histone deacetylase inhibitor NSC3852 as a potential novel drug for the treatment of pediatric acute myeloid leukemia

Wiggers

Govers

Lelieveld

et al. 2019

Pediatric Blood & Cancer

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“…As affinities for a number of BRDs have been experimentally determined by ITC (Table 2), 39 it is an ideal system to test the ability of free energy calculations to capture the affinity profile of a ligand across many similar binding pockets. As for RVX-OH and RVX-208, all bromodomains with at least a crystal structure available in the PDB and affinity data determined by ITC were considered, for a total of 22 bromosporine/BRD pairs.…”

Section: Resultsmentioning

confidence: 99%

Predictions of Ligand Selectivity from Absolute Binding Free Energy Calculations

et al. 2017

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Binding selectivity is a requirement for the development of a safe drug, and it is a critical property for chemical probes used in preclinical target validation. Engineering selectivity adds considerable complexity to the rational design of new drugs, as it involves the optimization of multiple binding affinities. Computationally, the prediction of binding selectivity is a challenge, and generally applicable methodologies are still not available to the computational and medicinal chemistry communities. Absolute binding free energy calculations based on alchemical pathways provide a rigorous framework for affinity predictions and could thus offer a general approach to the problem. We evaluated the performance of free energy calculations based on molecular dynamics for the prediction of selectivity by estimating the affinity profile of three bromodomain inhibitors across multiple bromodomain families, and by comparing the results to isothermal titration calorimetry data. Two case studies were considered. In the first one, the affinities of two similar ligands for seven bromodomains were calculated and returned excellent agreement with experiment (mean unsigned error of 0.81 kcal/mol and Pearson correlation of 0.75). In this test case, we also show how the preferred binding orientation of a ligand for different proteins can be estimated via free energy calculations. In the second case, the affinities of a broad-spectrum inhibitor for 22 bromodomains were calculated and returned a more modest accuracy (mean unsigned error of 1.76 kcal/mol and Pearson correlation of 0.48); however, the reparametrization of a sulfonamide moiety improved the agreement with experiment.

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“…Given their connection to a number of diseases, including cancer, inflammation, and viral infection, they have recently been the subject of intense efforts for the development of chemical probes aimed at their validation as drug targets [3][4][5][6] . Compounds targeting the bromodomain and extra-terminal (BET) family of bromodomains are currently already in clinical trials for the treatment of diverse malignancies, such as leukemia, nuclear protein of the testis (NUT) midline carcinoma, and progressive lymphoma 5 .…”

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confidence: 99%

Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo

et al. 2018

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Conserved water molecules are of interest in drug design, as displacement of such waters can lead to higher affinity ligands, and in some cases, contribute towards selectivity. Bromodomains, small protein domains involved in the epigenetic regulation of gene transcription, display a network of four conserved water molecules in their binding pockets and have recently been the focus of intense medicinal chemistry efforts. Understanding why certain bromodomains have displaceable water molecules and others do not is extremely challenging, and it remains unclear which water molecules in a given bromodomain can be targeted for displacement. Here we estimate the stability of the conserved water molecules in 35 bromodomains via binding free energy calculations using all-atom grand canonical Monte Carlo simulations. Encouraging quantitative agreement to the available experimental evidence is found. We thus discuss the expected ease of water displacement in different bromodomains and the implications for ligand selectivity.

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Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia

Abstract: BET bromodomains are unique targeting modules that mediate primary transcription response.

Cited by 101 publications

References 65 publications

Epigenetic drug screen identifies the histone deacetylase inhibitor NSC3852 as a potential novel drug for the treatment of pediatric acute myeloid leukemia

Epigenetic drug screen identifies the histone deacetylase inhibitor NSC3852 as a potential novel drug for the treatment of pediatric acute myeloid leukemia

Predictions of Ligand Selectivity from Absolute Binding Free Energy Calculations

Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo

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