Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer
Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains...
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| Veröffentlicht in: | Nature (London) 2020-02, Vol.578 (7794), p.306-310 |
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| creator | Faivre, Emily J. McDaniel, Keith F. Albert, Daniel H. Mantena, Srinivasa R. Plotnik, Joshua P. Wilcox, Denise Zhang, Lu Bui, Mai H. Sheppard, George S. Wang, Le Sehgal, Vasudha Lin, Xiaoyu Huang, Xiaoli Lu, Xin Uziel, Tamar Hessler, Paul Lam, Lloyd T. Bellin, Richard J. Mehta, Gaurav Fidanze, Steve Pratt, John K. Liu, Dachun Hasvold, Lisa A. Sun, Chaohong Panchal, Sanjay C. Nicolette, John J. Fossey, Stacey L. Park, Chang H. Longenecker, Kenton Bigelow, Lance Torrent, Maricel Rosenberg, Saul H. Kati, Warren M. Shen, Yu |
| description | Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi
1
–
5
. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of
Brd4
in mice
6
, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions
7
–
9
and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported
10
,
11
, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment
10
–
13
. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-075
14
. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.
ABBV-744, a selective inhibitor of the BD2 domains of BET family proteins, is effective against prostate cancer in mo |
| doi_str_mv | 10.1038/s41586-020-1930-8 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_osti_</sourceid><recordid>TN_cdi_osti_scitechconnect_1603173</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A660675767</galeid><sourcerecordid>A660675767</sourcerecordid><originalsourceid>FETCH-LOGICAL-c667t-d244f32db51b76aebac51f3c2b7af4a71db13305bc4240c15cc45500186cc7783</originalsourceid><addsrcrecordid>eNp10l1v0zAUBuAIgVgZ_ABuULRdIZRx_BE7vezKgEnTkFgRl5bjnLSeGruzXQT_HpcMWKVOuUjkPOfYyXmL4jWBMwKseR85qRtRAYWKTBlUzZNiQrgUFReNfFpMAGhTQcPEUfEixlsAqInkz4sjRqZiKoFOiusbXKNJ9geW1q1sa5P1rvR9mVZYnn-gZRv84Ds_aPtn-fxiUW6CT2hdzBW755h0wtJoZzC8LJ71eh3x1f39uPj28WIx_1xdffl0OZ9dVUYImaqOct4z2rU1aaXQ2GpTk54Z2krdcy1J1xLGoG4NpxwMqY3hdQ1AGmGMlA07Lk7Gvnl3q6KxCc3KeOfytygigBHJMjodUT7k3RZjUrd-G1w-l6JM0Ck0wB-opV6jsq73KWgz2GjUTAgQspZCZlUdUEt0GPTaO-xtXt7zJwe82dg79RCdHUD56nCw5mDXt3sF2ST8mZZ6G6O6vPm6b989bmeL7_PrfU1GbfJAY8BebYIddPilCKhd2NQYNpXDpnZhU7shvLn_v9t2wO5fxd90ZUBHEPMrt8TwfwCPd_0N7d_YRQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2362908043</pqid></control><display><type>article</type><title>Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer</title><source>MEDLINE</source><source>Nature Journals</source><source>SpringerLink (Online service)</source><creator>Faivre, Emily J. ; McDaniel, Keith F. ; Albert, Daniel H. ; Mantena, Srinivasa R. ; Plotnik, Joshua P. ; Wilcox, Denise ; Zhang, Lu ; Bui, Mai H. ; Sheppard, George S. ; Wang, Le ; Sehgal, Vasudha ; Lin, Xiaoyu ; Huang, Xiaoli ; Lu, Xin ; Uziel, Tamar ; Hessler, Paul ; Lam, Lloyd T. ; Bellin, Richard J. ; Mehta, Gaurav ; Fidanze, Steve ; Pratt, John K. ; Liu, Dachun ; Hasvold, Lisa A. ; Sun, Chaohong ; Panchal, Sanjay C. ; Nicolette, John J. ; Fossey, Stacey L. ; Park, Chang H. ; Longenecker, Kenton ; Bigelow, Lance ; Torrent, Maricel ; Rosenberg, Saul H. ; Kati, Warren M. ; Shen, Yu</creator><creatorcontrib>Faivre, Emily J. ; McDaniel, Keith F. ; Albert, Daniel H. ; Mantena, Srinivasa R. ; Plotnik, Joshua P. ; Wilcox, Denise ; Zhang, Lu ; Bui, Mai H. ; Sheppard, George S. ; Wang, Le ; Sehgal, Vasudha ; Lin, Xiaoyu ; Huang, Xiaoli ; Lu, Xin ; Uziel, Tamar ; Hessler, Paul ; Lam, Lloyd T. ; Bellin, Richard J. ; Mehta, Gaurav ; Fidanze, Steve ; Pratt, John K. ; Liu, Dachun ; Hasvold, Lisa A. ; Sun, Chaohong ; Panchal, Sanjay C. ; Nicolette, John J. ; Fossey, Stacey L. ; Park, Chang H. ; Longenecker, Kenton ; Bigelow, Lance ; Torrent, Maricel ; Rosenberg, Saul H. ; Kati, Warren M. ; Shen, Yu ; Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><description>Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi
1
–
5
. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of
Brd4
in mice
6
, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions
7
–
9
and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported
10
,
11
, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment
10
–
13
. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-075
14
. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.
ABBV-744, a selective inhibitor of the BD2 domains of BET family proteins, is effective against prostate cancer in mouse xenograft models, with lower toxicities than the dual-bromodomain BET inhibitor ABBV-075.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-020-1930-8</identifier><identifier>PMID: 31969702</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/106 ; 38/39 ; 45/15 ; 631/154 ; 631/67/1059 ; Acute myeloid leukemia ; Androgen receptors ; Animals ; Biocompatibility ; Care and treatment ; Cell cycle ; Cell Cycle Proteins - antagonists & inhibitors ; Cell Cycle Proteins - chemistry ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Chemical inhibitors ; Chromatin ; Clinical trials ; Enhancer Elements, Genetic - genetics ; Enhancers ; Epigenetic inheritance ; Epigenetics ; Gene expression ; Gene Expression Regulation, Neoplastic - drug effects ; Gene sequencing ; Genes ; Genetic aspects ; Growth inhibition ; Health aspects ; Histones ; Humanities and Social Sciences ; Humans ; Immunoprecipitation ; Kinases ; Leukemia ; Male ; Mice ; multidisciplinary ; Organic chemistry ; Pharmacokinetics ; Pharmacology ; Phenotypes ; Physiological aspects ; Platelets ; Prostate cancer ; Prostatic Neoplasms - drug therapy ; Prostatic Neoplasms - metabolism ; Protein Domains - drug effects ; Proteins ; Pyridines - adverse effects ; Pyridines - pharmacology ; Pyridines - toxicity ; Pyrroles - adverse effects ; Pyrroles - pharmacology ; Pyrroles - toxicity ; Rats ; Receptors, Androgen - metabolism ; Ribonucleic acid ; RNA ; Science ; Science (multidisciplinary) ; Thrombocytes ; Thrombocytopenia ; Toxicity ; Transcription ; Transcription Factors - antagonists & inhibitors ; Transcription Factors - chemistry ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transcription, Genetic - drug effects ; Xenograft Model Antitumor Assays ; Xenografts ; Xenotransplantation</subject><ispartof>Nature (London), 2020-02, Vol.578 (7794), p.306-310</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2020</rights><rights>COPYRIGHT 2020 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Feb 13, 2020</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c667t-d244f32db51b76aebac51f3c2b7af4a71db13305bc4240c15cc45500186cc7783</citedby><cites>FETCH-LOGICAL-c667t-d244f32db51b76aebac51f3c2b7af4a71db13305bc4240c15cc45500186cc7783</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41586-020-1930-8$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41586-020-1930-8$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31969702$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1603173$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Faivre, Emily J.</creatorcontrib><creatorcontrib>McDaniel, Keith F.</creatorcontrib><creatorcontrib>Albert, Daniel H.</creatorcontrib><creatorcontrib>Mantena, Srinivasa R.</creatorcontrib><creatorcontrib>Plotnik, Joshua P.</creatorcontrib><creatorcontrib>Wilcox, Denise</creatorcontrib><creatorcontrib>Zhang, Lu</creatorcontrib><creatorcontrib>Bui, Mai H.</creatorcontrib><creatorcontrib>Sheppard, George S.</creatorcontrib><creatorcontrib>Wang, Le</creatorcontrib><creatorcontrib>Sehgal, Vasudha</creatorcontrib><creatorcontrib>Lin, Xiaoyu</creatorcontrib><creatorcontrib>Huang, Xiaoli</creatorcontrib><creatorcontrib>Lu, Xin</creatorcontrib><creatorcontrib>Uziel, Tamar</creatorcontrib><creatorcontrib>Hessler, Paul</creatorcontrib><creatorcontrib>Lam, Lloyd T.</creatorcontrib><creatorcontrib>Bellin, Richard J.</creatorcontrib><creatorcontrib>Mehta, Gaurav</creatorcontrib><creatorcontrib>Fidanze, Steve</creatorcontrib><creatorcontrib>Pratt, John K.</creatorcontrib><creatorcontrib>Liu, Dachun</creatorcontrib><creatorcontrib>Hasvold, Lisa A.</creatorcontrib><creatorcontrib>Sun, Chaohong</creatorcontrib><creatorcontrib>Panchal, Sanjay C.</creatorcontrib><creatorcontrib>Nicolette, John J.</creatorcontrib><creatorcontrib>Fossey, Stacey L.</creatorcontrib><creatorcontrib>Park, Chang H.</creatorcontrib><creatorcontrib>Longenecker, Kenton</creatorcontrib><creatorcontrib>Bigelow, Lance</creatorcontrib><creatorcontrib>Torrent, Maricel</creatorcontrib><creatorcontrib>Rosenberg, Saul H.</creatorcontrib><creatorcontrib>Kati, Warren M.</creatorcontrib><creatorcontrib>Shen, Yu</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi
1
–
5
. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of
Brd4
in mice
6
, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions
7
–
9
and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported
10
,
11
, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment
10
–
13
. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-075
14
. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.
ABBV-744, a selective inhibitor of the BD2 domains of BET family proteins, is effective against prostate cancer in mouse xenograft models, with lower toxicities than the dual-bromodomain BET inhibitor ABBV-075.</description><subject>13/106</subject><subject>38/39</subject><subject>45/15</subject><subject>631/154</subject><subject>631/67/1059</subject><subject>Acute myeloid leukemia</subject><subject>Androgen receptors</subject><subject>Animals</subject><subject>Biocompatibility</subject><subject>Care and treatment</subject><subject>Cell cycle</subject><subject>Cell Cycle Proteins - antagonists & inhibitors</subject><subject>Cell Cycle Proteins - chemistry</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Chemical inhibitors</subject><subject>Chromatin</subject><subject>Clinical trials</subject><subject>Enhancer Elements, Genetic - genetics</subject><subject>Enhancers</subject><subject>Epigenetic inheritance</subject><subject>Epigenetics</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Gene sequencing</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Growth inhibition</subject><subject>Health aspects</subject><subject>Histones</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Male</subject><subject>Mice</subject><subject>multidisciplinary</subject><subject>Organic chemistry</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>Phenotypes</subject><subject>Physiological aspects</subject><subject>Platelets</subject><subject>Prostate cancer</subject><subject>Prostatic Neoplasms - drug therapy</subject><subject>Prostatic Neoplasms - metabolism</subject><subject>Protein Domains - drug effects</subject><subject>Proteins</subject><subject>Pyridines - adverse effects</subject><subject>Pyridines - pharmacology</subject><subject>Pyridines - toxicity</subject><subject>Pyrroles - adverse effects</subject><subject>Pyrroles - pharmacology</subject><subject>Pyrroles - toxicity</subject><subject>Rats</subject><subject>Receptors, Androgen - metabolism</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Thrombocytes</subject><subject>Thrombocytopenia</subject><subject>Toxicity</subject><subject>Transcription</subject><subject>Transcription Factors - antagonists & inhibitors</subject><subject>Transcription Factors - chemistry</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Transcription, Genetic - drug effects</subject><subject>Xenograft Model Antitumor 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inhibition of the BD2 bromodomain of BET proteins in prostate cancer</title><author>Faivre, Emily J. ; McDaniel, Keith F. ; Albert, Daniel H. ; Mantena, Srinivasa R. ; Plotnik, Joshua P. ; Wilcox, Denise ; Zhang, Lu ; Bui, Mai H. ; Sheppard, George S. ; Wang, Le ; Sehgal, Vasudha ; Lin, Xiaoyu ; Huang, Xiaoli ; Lu, Xin ; Uziel, Tamar ; Hessler, Paul ; Lam, Lloyd T. ; Bellin, Richard J. ; Mehta, Gaurav ; Fidanze, Steve ; Pratt, John K. ; Liu, Dachun ; Hasvold, Lisa A. ; Sun, Chaohong ; Panchal, Sanjay C. ; Nicolette, John J. ; Fossey, Stacey L. ; Park, Chang H. ; Longenecker, Kenton ; Bigelow, Lance ; Torrent, Maricel ; Rosenberg, Saul H. ; Kati, Warren M. ; Shen, Yu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c667t-d244f32db51b76aebac51f3c2b7af4a71db13305bc4240c15cc45500186cc7783</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>13/106</topic><topic>38/39</topic><topic>45/15</topic><topic>631/154</topic><topic>631/67/1059</topic><topic>Acute myeloid leukemia</topic><topic>Androgen receptors</topic><topic>Animals</topic><topic>Biocompatibility</topic><topic>Care and treatment</topic><topic>Cell cycle</topic><topic>Cell Cycle Proteins - antagonists & inhibitors</topic><topic>Cell Cycle Proteins - chemistry</topic><topic>Cell Cycle Proteins - genetics</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Chemical inhibitors</topic><topic>Chromatin</topic><topic>Clinical trials</topic><topic>Enhancer Elements, Genetic - genetics</topic><topic>Enhancers</topic><topic>Epigenetic inheritance</topic><topic>Epigenetics</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Gene sequencing</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Growth inhibition</topic><topic>Health aspects</topic><topic>Histones</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Immunoprecipitation</topic><topic>Kinases</topic><topic>Leukemia</topic><topic>Male</topic><topic>Mice</topic><topic>multidisciplinary</topic><topic>Organic chemistry</topic><topic>Pharmacokinetics</topic><topic>Pharmacology</topic><topic>Phenotypes</topic><topic>Physiological aspects</topic><topic>Platelets</topic><topic>Prostate cancer</topic><topic>Prostatic Neoplasms - drug therapy</topic><topic>Prostatic Neoplasms - metabolism</topic><topic>Protein Domains - drug effects</topic><topic>Proteins</topic><topic>Pyridines - adverse effects</topic><topic>Pyridines - pharmacology</topic><topic>Pyridines - toxicity</topic><topic>Pyrroles - adverse effects</topic><topic>Pyrroles - pharmacology</topic><topic>Pyrroles - toxicity</topic><topic>Rats</topic><topic>Receptors, Androgen - metabolism</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Thrombocytes</topic><topic>Thrombocytopenia</topic><topic>Toxicity</topic><topic>Transcription</topic><topic>Transcription Factors - antagonists & inhibitors</topic><topic>Transcription Factors - chemistry</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Transcription, Genetic - drug effects</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Xenografts</topic><topic>Xenotransplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Faivre, Emily J.</creatorcontrib><creatorcontrib>McDaniel, Keith F.</creatorcontrib><creatorcontrib>Albert, Daniel H.</creatorcontrib><creatorcontrib>Mantena, Srinivasa R.</creatorcontrib><creatorcontrib>Plotnik, Joshua P.</creatorcontrib><creatorcontrib>Wilcox, Denise</creatorcontrib><creatorcontrib>Zhang, Lu</creatorcontrib><creatorcontrib>Bui, Mai H.</creatorcontrib><creatorcontrib>Sheppard, George S.</creatorcontrib><creatorcontrib>Wang, Le</creatorcontrib><creatorcontrib>Sehgal, Vasudha</creatorcontrib><creatorcontrib>Lin, Xiaoyu</creatorcontrib><creatorcontrib>Huang, Xiaoli</creatorcontrib><creatorcontrib>Lu, Xin</creatorcontrib><creatorcontrib>Uziel, Tamar</creatorcontrib><creatorcontrib>Hessler, Paul</creatorcontrib><creatorcontrib>Lam, Lloyd T.</creatorcontrib><creatorcontrib>Bellin, Richard J.</creatorcontrib><creatorcontrib>Mehta, Gaurav</creatorcontrib><creatorcontrib>Fidanze, Steve</creatorcontrib><creatorcontrib>Pratt, John K.</creatorcontrib><creatorcontrib>Liu, Dachun</creatorcontrib><creatorcontrib>Hasvold, Lisa A.</creatorcontrib><creatorcontrib>Sun, Chaohong</creatorcontrib><creatorcontrib>Panchal, Sanjay C.</creatorcontrib><creatorcontrib>Nicolette, John J.</creatorcontrib><creatorcontrib>Fossey, Stacey L.</creatorcontrib><creatorcontrib>Park, Chang H.</creatorcontrib><creatorcontrib>Longenecker, Kenton</creatorcontrib><creatorcontrib>Bigelow, Lance</creatorcontrib><creatorcontrib>Torrent, Maricel</creatorcontrib><creatorcontrib>Rosenberg, Saul H.</creatorcontrib><creatorcontrib>Kati, Warren M.</creatorcontrib><creatorcontrib>Shen, Yu</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Middle School</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>ProQuest Nursing and Allied Health Journals</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Environment Abstracts</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>ProQuest Agriculture & Environmental Science Database</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Earth, Atmospheric & Aquatic Science Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>Biological Sciences</collection><collection>Agriculture Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest Psychology</collection><collection>Research Library (ProQuest)</collection><collection>ProQuest Science Journals</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>ProQuest Engineering Database</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>ProQuest Earth, Atmospheric & Aquatic Science Database</collection><collection>Materials Science Collection</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest One Psychology</collection><collection>Engineering collection</collection><collection>Environmental Science Collection</collection><collection>ProQuest Central Basic</collection><collection>University of Michigan</collection><collection>Genetics Abstracts</collection><collection>SIRS Editorial</collection><collection>Environment Abstracts</collection><collection>OSTI.GOV</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Faivre, Emily J.</au><au>McDaniel, Keith F.</au><au>Albert, Daniel H.</au><au>Mantena, Srinivasa R.</au><au>Plotnik, Joshua P.</au><au>Wilcox, Denise</au><au>Zhang, Lu</au><au>Bui, Mai H.</au><au>Sheppard, George S.</au><au>Wang, Le</au><au>Sehgal, Vasudha</au><au>Lin, Xiaoyu</au><au>Huang, Xiaoli</au><au>Lu, Xin</au><au>Uziel, Tamar</au><au>Hessler, Paul</au><au>Lam, Lloyd T.</au><au>Bellin, Richard J.</au><au>Mehta, Gaurav</au><au>Fidanze, Steve</au><au>Pratt, John K.</au><au>Liu, Dachun</au><au>Hasvold, Lisa A.</au><au>Sun, Chaohong</au><au>Panchal, Sanjay C.</au><au>Nicolette, John J.</au><au>Fossey, Stacey L.</au><au>Park, Chang H.</au><au>Longenecker, Kenton</au><au>Bigelow, Lance</au><au>Torrent, Maricel</au><au>Rosenberg, Saul H.</au><au>Kati, Warren M.</au><au>Shen, Yu</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2020-02-13</date><risdate>2020</risdate><volume>578</volume><issue>7794</issue><spage>306</spage><epage>310</epage><pages>306-310</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi
1
–
5
. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of
Brd4
in mice
6
, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions
7
–
9
and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported
10
,
11
, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment
10
–
13
. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-075
14
. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.
ABBV-744, a selective inhibitor of the BD2 domains of BET family proteins, is effective against prostate cancer in mouse xenograft models, with lower toxicities than the dual-bromodomain BET inhibitor ABBV-075.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31969702</pmid><doi>10.1038/s41586-020-1930-8</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2020-02, Vol.578 (7794), p.306-310 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_osti_scitechconnect_1603173 |
| source | MEDLINE; Nature Journals; SpringerLink (Online service) |
| subjects | 13/106 38/39 45/15 631/154 631/67/1059 Acute myeloid leukemia Androgen receptors Animals Biocompatibility Care and treatment Cell cycle Cell Cycle Proteins - antagonists & inhibitors Cell Cycle Proteins - chemistry Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell Line, Tumor Cell Proliferation - drug effects Chemical inhibitors Chromatin Clinical trials Enhancer Elements, Genetic - genetics Enhancers Epigenetic inheritance Epigenetics Gene expression Gene Expression Regulation, Neoplastic - drug effects Gene sequencing Genes Genetic aspects Growth inhibition Health aspects Histones Humanities and Social Sciences Humans Immunoprecipitation Kinases Leukemia Male Mice multidisciplinary Organic chemistry Pharmacokinetics Pharmacology Phenotypes Physiological aspects Platelets Prostate cancer Prostatic Neoplasms - drug therapy Prostatic Neoplasms - metabolism Protein Domains - drug effects Proteins Pyridines - adverse effects Pyridines - pharmacology Pyridines - toxicity Pyrroles - adverse effects Pyrroles - pharmacology Pyrroles - toxicity Rats Receptors, Androgen - metabolism Ribonucleic acid RNA Science Science (multidisciplinary) Thrombocytes Thrombocytopenia Toxicity Transcription Transcription Factors - antagonists & inhibitors Transcription Factors - chemistry Transcription Factors - genetics Transcription Factors - metabolism Transcription, Genetic - drug effects Xenograft Model Antitumor Assays Xenografts Xenotransplantation |
| title | Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer |
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