The Experts below are selected from a list of 13536 Experts worldwide ranked by ideXlab platform
Paul Harrington - One of the best experts on this subject based on the ideXlab platform.
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exploration of the internal cavity of histone deacetylase hdac with selective HDAC1 hdac2 inhibitors shi 1 2
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: Joey L Methot, Prasun K Chakravarty, Melissa Chenard, Joshua Close, Jonathan C Cruz, William K Dahlberg, Judith C Fleming, Christopher Hamblett, Julie E Hamill, Paul HarringtonAbstract:We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.
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optimization of biaryl selective HDAC1 2 inhibitors shi 1 2
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: David J Witter, Melissa Chenard, Judith C Fleming, Paul Harrington, Kevin J Wilson, Brian B Haines, Astrid M Kral, Paul J Secrist, Thomas A MillerAbstract:A class of biaryl benzamides was identified and optimized as selective HDAC1&2 inhibitors (SHI-1:2). These agents exhibit selectivity over class II HDACs 4–7, as well as class I HDACs 3 and 8; providing examples of selective HDAC inhibitors for the HDAC isoforms most closely associated with cancer. The hypothesis for the increased selectivity is the binding of a pendant aromatic group in the internal cavity of the HDAC1&2 enzymes. SAR development based on an initial lead led to a series of potent and selective inhibitors with reduced off-target activity and tumor growth inhibition activity in a HCT-116 xenograft model.
Stacey M Frumm - One of the best experts on this subject based on the ideXlab platform.
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selective HDAC1 hdac2 inhibitors induce neuroblastoma differentiation
Chemistry & Biology, 2013Co-Authors: Florence F Wagner, Stacey M Frumm, Kenneth N Ross, Jeremy R Duvall, Supriya Gupta, Lynn Verplank, Edward B Holson, William B Smith, Ronald M ParanalAbstract:Summary While cytotoxic chemotherapy remains the hallmark of cancer treatment, intensive regimens fall short in many malignancies, including high-risk neuroblastoma. One alternative strategy is to therapeutically promote tumor differentiation. We created a gene expression signature to measure neuroblast maturation, adapted it to a high-throughput platform, and screened a diversity oriented synthesis-generated small-molecule library for differentiation inducers. We identified BRD8430, containing a nine-membered lactam, an ortho-amino anilide functionality, and three chiral centers, as a selective class I histone deacetylase (HDAC) inhibitor (HDAC1 > 2 > 3). Further investigation demonstrated that selective HDAC1/HDAC2 inhibition using compounds or RNA interference induced differentiation and decreased viability in neuroblastoma cell lines. Combined treatment with 13- cis retinoic acid augmented these effects and enhanced activation of retinoic acid signaling. Therefore, by applying a chemical genomic screening approach, we identified selective HDAC1/HDAC2 inhibition as a strategy to induce neuroblastoma differentiation.
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Selective HDAC1/HDAC2 Inhibitors Induce Neuroblastoma Differentiation
Chemistry & Biology, 2013Co-Authors: Stacey M Frumm, Florence F Wagner, Kenneth N Ross, Jeremy R Duvall, Supriya Gupta, Lynn Verplank, Edward B Holson, William B SmithAbstract:Summary While cytotoxic chemotherapy remains the hallmark of cancer treatment, intensive regimens fall short in many malignancies, including high-risk neuroblastoma. One alternative strategy is to therapeutically promote tumor differentiation. We created a gene expression signature to measure neuroblast maturation, adapted it to a high-throughput platform, and screened a diversity oriented synthesis-generated small-molecule library for differentiation inducers. We identified BRD8430, containing a nine-membered lactam, an ortho-amino anilide functionality, and three chiral centers, as a selective class I histone deacetylase (HDAC) inhibitor (HDAC1 > 2 > 3). Further investigation demonstrated that selective HDAC1/HDAC2 inhibition using compounds or RNA interference induced differentiation and decreased viability in neuroblastoma cell lines. Combined treatment with 13- cis retinoic acid augmented these effects and enhanced activation of retinoic acid signaling. Therefore, by applying a chemical genomic screening approach, we identified selective HDAC1/HDAC2 inhibition as a strategy to induce neuroblastoma differentiation.
Florence F Wagner - One of the best experts on this subject based on the ideXlab platform.
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kinetic and structural insights into the binding of histone deacetylase 1 and 2 HDAC1 2 inhibitors
Bioorganic & Medicinal Chemistry, 2016Co-Authors: Florence F Wagner, Michel Weiwer, Stefan Steinbacher, Adrian Schomburg, Peter Reinemer, Jennifer Gale, Arthur J Campbell, Stewart L Fisher, Wenning Zhao, Surya A ReisAbstract:The structure-activity and structure-kinetic relationships of a series of novel and selective ortho-aminoanilide inhibitors of histone deacetylases (HDACs) 1 and 2 are described. Different kinetic and thermodynamic selectivity profiles were obtained by varying the moiety occupying an 11A channel leading to the Zn(2+) catalytic pocket of HDACs 1 and 2, two paralogs with a high degree of structural similarity. The design of these novel inhibitors was informed by two ligand-bound crystal structures of truncated hHDAC2. BRD4884 and BRD7232 possess kinetic selectivity for HDAC1 versus HDAC2. We demonstrate that the binding kinetics of HDAC inhibitors can be tuned for individual isoforms in order to modulate target residence time while retaining functional activity and increased histone H4K12 and H3K9 acetylation in primary mouse neuronal cell culture assays. These chromatin modifiers, with tuned binding kinetic profiles, can be used to define the relation between target engagement requirements and the pharmacodynamic response of HDACs in different disease applications.
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selective HDAC1 hdac2 inhibitors induce neuroblastoma differentiation
Chemistry & Biology, 2013Co-Authors: Florence F Wagner, Stacey M Frumm, Kenneth N Ross, Jeremy R Duvall, Supriya Gupta, Lynn Verplank, Edward B Holson, William B Smith, Ronald M ParanalAbstract:Summary While cytotoxic chemotherapy remains the hallmark of cancer treatment, intensive regimens fall short in many malignancies, including high-risk neuroblastoma. One alternative strategy is to therapeutically promote tumor differentiation. We created a gene expression signature to measure neuroblast maturation, adapted it to a high-throughput platform, and screened a diversity oriented synthesis-generated small-molecule library for differentiation inducers. We identified BRD8430, containing a nine-membered lactam, an ortho-amino anilide functionality, and three chiral centers, as a selective class I histone deacetylase (HDAC) inhibitor (HDAC1 > 2 > 3). Further investigation demonstrated that selective HDAC1/HDAC2 inhibition using compounds or RNA interference induced differentiation and decreased viability in neuroblastoma cell lines. Combined treatment with 13- cis retinoic acid augmented these effects and enhanced activation of retinoic acid signaling. Therefore, by applying a chemical genomic screening approach, we identified selective HDAC1/HDAC2 inhibition as a strategy to induce neuroblastoma differentiation.
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Selective HDAC1/HDAC2 Inhibitors Induce Neuroblastoma Differentiation
Chemistry & Biology, 2013Co-Authors: Stacey M Frumm, Florence F Wagner, Kenneth N Ross, Jeremy R Duvall, Supriya Gupta, Lynn Verplank, Edward B Holson, William B SmithAbstract:Summary While cytotoxic chemotherapy remains the hallmark of cancer treatment, intensive regimens fall short in many malignancies, including high-risk neuroblastoma. One alternative strategy is to therapeutically promote tumor differentiation. We created a gene expression signature to measure neuroblast maturation, adapted it to a high-throughput platform, and screened a diversity oriented synthesis-generated small-molecule library for differentiation inducers. We identified BRD8430, containing a nine-membered lactam, an ortho-amino anilide functionality, and three chiral centers, as a selective class I histone deacetylase (HDAC) inhibitor (HDAC1 > 2 > 3). Further investigation demonstrated that selective HDAC1/HDAC2 inhibition using compounds or RNA interference induced differentiation and decreased viability in neuroblastoma cell lines. Combined treatment with 13- cis retinoic acid augmented these effects and enhanced activation of retinoic acid signaling. Therefore, by applying a chemical genomic screening approach, we identified selective HDAC1/HDAC2 inhibition as a strategy to induce neuroblastoma differentiation.
Ronald M Paranal - One of the best experts on this subject based on the ideXlab platform.
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selective HDAC1 hdac2 inhibitors induce neuroblastoma differentiation
Chemistry & Biology, 2013Co-Authors: Florence F Wagner, Stacey M Frumm, Kenneth N Ross, Jeremy R Duvall, Supriya Gupta, Lynn Verplank, Edward B Holson, William B Smith, Ronald M ParanalAbstract:Summary While cytotoxic chemotherapy remains the hallmark of cancer treatment, intensive regimens fall short in many malignancies, including high-risk neuroblastoma. One alternative strategy is to therapeutically promote tumor differentiation. We created a gene expression signature to measure neuroblast maturation, adapted it to a high-throughput platform, and screened a diversity oriented synthesis-generated small-molecule library for differentiation inducers. We identified BRD8430, containing a nine-membered lactam, an ortho-amino anilide functionality, and three chiral centers, as a selective class I histone deacetylase (HDAC) inhibitor (HDAC1 > 2 > 3). Further investigation demonstrated that selective HDAC1/HDAC2 inhibition using compounds or RNA interference induced differentiation and decreased viability in neuroblastoma cell lines. Combined treatment with 13- cis retinoic acid augmented these effects and enhanced activation of retinoic acid signaling. Therefore, by applying a chemical genomic screening approach, we identified selective HDAC1/HDAC2 inhibition as a strategy to induce neuroblastoma differentiation.
Melissa Chenard - One of the best experts on this subject based on the ideXlab platform.
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exploration of the internal cavity of histone deacetylase hdac with selective HDAC1 hdac2 inhibitors shi 1 2
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: Joey L Methot, Prasun K Chakravarty, Melissa Chenard, Joshua Close, Jonathan C Cruz, William K Dahlberg, Judith C Fleming, Christopher Hamblett, Julie E Hamill, Paul HarringtonAbstract:We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.
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optimization of biaryl selective HDAC1 2 inhibitors shi 1 2
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: David J Witter, Melissa Chenard, Judith C Fleming, Paul Harrington, Kevin J Wilson, Brian B Haines, Astrid M Kral, Paul J Secrist, Thomas A MillerAbstract:A class of biaryl benzamides was identified and optimized as selective HDAC1&2 inhibitors (SHI-1:2). These agents exhibit selectivity over class II HDACs 4–7, as well as class I HDACs 3 and 8; providing examples of selective HDAC inhibitors for the HDAC isoforms most closely associated with cancer. The hypothesis for the increased selectivity is the binding of a pendant aromatic group in the internal cavity of the HDAC1&2 enzymes. SAR development based on an initial lead led to a series of potent and selective inhibitors with reduced off-target activity and tumor growth inhibition activity in a HCT-116 xenograft model.
