Structure‐Guided Synthesis and Evaluation of Small‐Molecule Inhibitors Targeting Protein–Protein Interactions of BRCA1 tBRCT Domain

The tandem BRCT domains (tBRCT) of BRCA1 engage phosphoserine‐containing motifs in target proteins to propagate intracellular signals initiated by DNA damage, thereby controlling cell cycle arrest and DNA repair. Recently, we identified Bractoppin, the first small‐molecule inhibitor of the BRCA1 tBR...

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Veröffentlicht in:ChemMedChem 2019-09, Vol.14 (18), p.1620-1632
Hauptverfasser: Kurdekar, Vadiraj, Giridharan, Saranya, Subbarao, Jasti, Nijaguna, Mamatha B., Periasamy, Jayaprakash, Boggaram, Sanjana, Shivange, Amol V., Sadasivam, Gayathri, Padigaru, Muralidhara, Potluri, Vijay, Venkitaraman, Ashok R., Bharatham, Kavitha
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container_end_page 1632
container_issue 18
container_start_page 1620
container_title ChemMedChem
container_volume 14
creator Kurdekar, Vadiraj
Giridharan, Saranya
Subbarao, Jasti
Nijaguna, Mamatha B.
Periasamy, Jayaprakash
Boggaram, Sanjana
Shivange, Amol V.
Sadasivam, Gayathri
Padigaru, Muralidhara
Potluri, Vijay
Venkitaraman, Ashok R.
Bharatham, Kavitha
description The tandem BRCT domains (tBRCT) of BRCA1 engage phosphoserine‐containing motifs in target proteins to propagate intracellular signals initiated by DNA damage, thereby controlling cell cycle arrest and DNA repair. Recently, we identified Bractoppin, the first small‐molecule inhibitor of the BRCA1 tBRCT domain, which selectively interrupts BRCA1‐mediated cellular responses evoked by DNA damage. Here, we combine structure‐guided chemical elaboration, protein mutagenesis and cellular assays to define the structural features responsible for Bractoppin's activity. Bractoppin fails to bind mutant forms of BRCA1 tBRCT bearing K1702A, a key residue mediating phosphopeptide recognition, or F1662R or L1701K that adjoin the pSer‐recognition site. However, the M1775R mutation, which engages the Phe residue in the consensus phosphopeptide motif pSer‐X‐X‐Phe, does not affect Bractoppin binding, confirming a binding mode distinct from the substrate phosphopeptide binding. We explored these structural features through structure‐guided chemical elaboration and characterized structure–activity relationships (SARs) in biochemical assays. Two analogues, CCBT2088 and CCBT2103 were effective in abrogating BRCA1 foci formation and inhibiting G2 arrest induced by irradiation of cells. Collectively, our findings reveal structural features underlying the activity of a novel inhibitor of phosphopeptide recognition by the BRCA1 tBRCT domain, providing fresh insights to guide the development of inhibitors that target protein–protein interactions. Taming BRCA1 by its tail, tBRCT: Bractoppin blocks the phosphopeptide‐binding site of BRCA1 via structural features distinct from the substrate phosphopeptide. Chemical elaboration conceptualized from mutagenesis and structure‐guided strategies reveal structural features underlying the biochemical potency of Bractoppin analogs against BRCA1 tBRCT domain. This expands the scope of developing inhibitors targeting protein–protein interactions.
doi_str_mv 10.1002/cmdc.201900300
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Recently, we identified Bractoppin, the first small‐molecule inhibitor of the BRCA1 tBRCT domain, which selectively interrupts BRCA1‐mediated cellular responses evoked by DNA damage. Here, we combine structure‐guided chemical elaboration, protein mutagenesis and cellular assays to define the structural features responsible for Bractoppin's activity. Bractoppin fails to bind mutant forms of BRCA1 tBRCT bearing K1702A, a key residue mediating phosphopeptide recognition, or F1662R or L1701K that adjoin the pSer‐recognition site. However, the M1775R mutation, which engages the Phe residue in the consensus phosphopeptide motif pSer‐X‐X‐Phe, does not affect Bractoppin binding, confirming a binding mode distinct from the substrate phosphopeptide binding. We explored these structural features through structure‐guided chemical elaboration and characterized structure–activity relationships (SARs) in biochemical assays. Two analogues, CCBT2088 and CCBT2103 were effective in abrogating BRCA1 foci formation and inhibiting G2 arrest induced by irradiation of cells. Collectively, our findings reveal structural features underlying the activity of a novel inhibitor of phosphopeptide recognition by the BRCA1 tBRCT domain, providing fresh insights to guide the development of inhibitors that target protein–protein interactions. Taming BRCA1 by its tail, tBRCT: Bractoppin blocks the phosphopeptide‐binding site of BRCA1 via structural features distinct from the substrate phosphopeptide. Chemical elaboration conceptualized from mutagenesis and structure‐guided strategies reveal structural features underlying the biochemical potency of Bractoppin analogs against BRCA1 tBRCT domain. 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Two analogues, CCBT2088 and CCBT2103 were effective in abrogating BRCA1 foci formation and inhibiting G2 arrest induced by irradiation of cells. Collectively, our findings reveal structural features underlying the activity of a novel inhibitor of phosphopeptide recognition by the BRCA1 tBRCT domain, providing fresh insights to guide the development of inhibitors that target protein–protein interactions. Taming BRCA1 by its tail, tBRCT: Bractoppin blocks the phosphopeptide‐binding site of BRCA1 via structural features distinct from the substrate phosphopeptide. Chemical elaboration conceptualized from mutagenesis and structure‐guided strategies reveal structural features underlying the biochemical potency of Bractoppin analogs against BRCA1 tBRCT domain. 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Two analogues, CCBT2088 and CCBT2103 were effective in abrogating BRCA1 foci formation and inhibiting G2 arrest induced by irradiation of cells. Collectively, our findings reveal structural features underlying the activity of a novel inhibitor of phosphopeptide recognition by the BRCA1 tBRCT domain, providing fresh insights to guide the development of inhibitors that target protein–protein interactions. Taming BRCA1 by its tail, tBRCT: Bractoppin blocks the phosphopeptide‐binding site of BRCA1 via structural features distinct from the substrate phosphopeptide. Chemical elaboration conceptualized from mutagenesis and structure‐guided strategies reveal structural features underlying the biochemical potency of Bractoppin analogs against BRCA1 tBRCT domain. 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identifier ISSN: 1860-7179
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subjects Binding
BRCA1
BRCA1 protein
BRCT domain
Breast cancer
Cell cycle
Cellular structure
Chemical synthesis
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
GIST
Homologous recombination
Inhibitors
Irradiation
Mutagenesis
Mutation
Organic chemistry
Phosphoserine
Protein interaction
Protein structure
Proteins
Protein–protein interactions
Structural damage
Substrates
title Structure‐Guided Synthesis and Evaluation of Small‐Molecule Inhibitors Targeting Protein–Protein Interactions of BRCA1 tBRCT Domain
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