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Isoform-Selective ATAD2 Chemical Probe with Novel Chemical Structure and Unusual Mode of Action.

ABSTRACT: ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones in vitro, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biology.

SUBMITTER: Fernandez-Montalvan AE

PROVIDER: S-EPMC6218015 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Isoform-Selective ATAD2 Chemical Probe with Novel Chemical Structure and Unusual Mode of Action.

Fernández-Montalván Amaury E AE Berger Markus M Kuropka Benno B Koo Seong Joo SJ Badock Volker V Weiske Joerg J Puetter Vera V Holton Simon J SJ Stöckigt Detlef D Ter Laak Antonius A Centrella Paolo A PA Clark Matthew A MA Dumelin Christoph E CE Sigel Eric A EA Soutter Holly H HH Troast Dawn M DM Zhang Ying Y Cuozzo John W JW Keefe Anthony D AD Roche Didier D Rodeschini Vincent V Chaikuad Apirat A Díaz-Sáez Laura L Bennett James M JM Fedorov Oleg O Huber Kilian V M KVM Hübner Jan J Weinmann Hilmar H Hartung Ingo V IV Gorjánácz Mátyás M

ACS chemical biology 20171024 11

ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones in vitro, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biolog ...[more]

PMID: 29043777

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Project description:Cervimycins A-D are bis-glycosylated polyketide antibiotics produced by Streptomyces tendae HKI 0179 with bactericidal activity against Gram-positive bacteria. In this study, cervimycin C (CmC) treatment caused a spaghetti-like phenotype in Bacillus subtilis 168, with elongated curved cells, which stayed joined after cell division, and exhibited a chromosome segregation defect, resulting in ghost cells without DNA. Electron microscopy of cervimycin treated S. aureus (3 x MIC) revealed swollen cells, misshapen septa, cell wall thickening, and a rough cell wall surface. Incorporation tests in B. subtilis indicated an effect on DNA biosynthesis at high cervimycin concentrations. Indeed, artificial down-regulation of the DNA gyrase subunit B gene (gyrB) increased the activity of cervimycin in agar diffusion tests, and, in high concentrations (starting at 62.5 x MIC), the antibiotic inhibited S. aureus DNA gyrase supercoiling activity in vitro. To obtain a more global view on the mode of action of CmC, transcriptomics and proteomics of cervimycin treated versus untreated S. aureus cells were performed. Interestingly, 3 x MIC of cervimycin did not induce the SOS response, which would indicate disturbance of the DNA gyrase activity in vivo. Instead, cervimycin induced the expression of the CtsR/HrcA heat shock operon and the expression of autolysins, exhibiting similarity to the ribosome-targeting gentamicin. In summary, we identified the DNA gyrase as a target, but at low concentrations electron microscopy and omics data revealed a more complex mode of action of cervimycin, that comprised induction of the heat shock response, indicating protein stress in the cell. A synergistic effect was seen when sodium chloride (NaCl) was added during cervimycin MIC testing of S. aureus SG511. Thus, transcriptomics of S. aureus cells under osmotic stress (1 M NaCl) were performed. The stress response was compared to the cervimycin stress response to identify factors which might contribute to the synergistic antibacterial effect of the two molecules.

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Isoform-Selective ATAD2 Chemical Probe with Novel Chemical Structure and Unusual Mode of Action.

Publications

Isoform-Selective ATAD2 Chemical Probe with Novel Chemical Structure and Unusual Mode of Action.

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