{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T08:09:11Z","timestamp":1792656551216,"version":"4.5.0"},"reference-count":23,"publisher":"National Academy of Sciences","issue":"40","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,10,4]]},"abstract":"<jats:p>\n                    The MYC transcription factor is a master regulator of diverse cellular functions and has been long considered a compelling therapeutic target because of its role in a range of human malignancies. However, pharmacologic inhibition of MYC function has proven challenging because of both the diverse mechanisms driving its aberrant expression and the challenge of disrupting protein\u2013DNA interactions. Here, we demonstrate the rapid and potent abrogation of\n                    <jats:italic>MYC<\/jats:italic>\n                    gene transcription by representative small molecule inhibitors of the BET family of chromatin adaptors.\n                    <jats:italic>MYC<\/jats:italic>\n                    transcriptional suppression was observed in the context of the natural, chromosomally translocated, and amplified gene locus. Inhibition of BET bromodomain\u2013promoter interactions and subsequent reduction of\n                    <jats:italic>MYC<\/jats:italic>\n                    transcript and protein levels resulted in G\n                    <jats:sub>1<\/jats:sub>\n                    arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines. Exogenous expression of\n                    <jats:italic>MYC<\/jats:italic>\n                    from an artificial promoter that is resistant to BET regulation significantly protected cells from cell cycle arrest and growth suppression by BET inhibitors.\n                    <jats:italic>MYC<\/jats:italic>\n                    suppression was accompanied by deregulation of the MYC transcriptome, including potent reactivation of the\n                    <jats:italic>p21<\/jats:italic>\n                    tumor suppressor. Treatment with a BET inhibitor resulted in significant antitumor activity in xenograft models of Burkitt's lymphoma and acute myeloid leukemia. These findings demonstrate that pharmacologic inhibition of\n                    <jats:italic>MYC<\/jats:italic>\n                    is achievable through targeting BET bromodomains. Such inhibitors may have clinical utility given the widespread pathogenetic role of\n                    <jats:italic>MYC<\/jats:italic>\n                    in cancer.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1108190108","type":"journal-article","created":{"date-parts":[[2011,9,27]],"date-time":"2011-09-27T02:26:14Z","timestamp":1317090374000},"page":"16669-16674","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1031,"title":["Targeting MYC dependence in cancer by inhibiting BET bromodomains"],"prefix":"10.1073","volume":"108","author":[{"given":"Jennifer A.","family":"Mertz","sequence":"first","affiliation":[{"name":"Constellation Pharmaceuticals, Inc., Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew R.","family":"Conery","sequence":"additional","affiliation":[{"name":"Constellation Pharmaceuticals, Inc., Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara M.","family":"Bryant","sequence":"additional","affiliation":[{"name":"Constellation Pharmaceuticals, Inc., Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Sandy","sequence":"additional","affiliation":[{"name":"Constellation Pharmaceuticals, Inc., Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srividya","family":"Balasubramanian","sequence":"additional","affiliation":[{"name":"Constellation Pharmaceuticals, Inc., Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deanna A.","family":"Mele","sequence":"additional","affiliation":[{"name":"Constellation Pharmaceuticals, Inc., Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Bergeron","sequence":"additional","affiliation":[{"name":"Constellation Pharmaceuticals, Inc., Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Robert J.","family":"Sims","sequence":"additional","affiliation":[{"name":"Constellation Pharmaceuticals, Inc., Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,9,26]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"13141","DOI":"10.1074\/jbc.R700001200","article-title":"The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation","volume":"282","author":"Wu SY","year":"2007","unstructured":"SY Wu, CM Chiang, The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation. J Biol Chem 282, 13141\u201313145 (2007).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"2437","DOI":"10.1101\/gad.1235904","article-title":"Elongation by RNA polymerase II: The short and long of it","volume":"18","author":"Sims RJ","year":"2004","unstructured":"RJ Sims, R Belotserkovskaya, D Reinberg, Elongation by RNA polymerase II: The short and long of it. Genes Dev 18, 2437\u20132468 (2004).","journal-title":"Genes Dev"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1128\/MCB.01020-07","article-title":"Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression","volume":"28","author":"Yang Z","year":"2008","unstructured":"Z Yang, N He, Q Zhou, Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression. Mol Cell Biol 28, 967\u2013976 (2008).","journal-title":"Mol Cell Biol"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"4899","DOI":"10.1091\/mbc.e09-05-0380","article-title":"Brd4 marks select genes on mitotic chromatin and directs postmitotic transcription","volume":"20","author":"Dey A","year":"2009","unstructured":"A Dey, A Nishiyama, T Karpova, J McNally, K Ozato, Brd4 marks select genes on mitotic chromatin and directs postmitotic transcription. Mol Biol Cell 20, 4899\u20134909 (2009).","journal-title":"Mol Biol Cell"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.molcel.2008.01.018","article-title":"The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription","volume":"30","author":"LeRoy G","year":"2008","unstructured":"G LeRoy, B Rickards, SJ Flint, The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol Cell 30, 51\u201360 (2008).","journal-title":"Mol Cell"},{"key":"e_1_3_4_6_2","unstructured":"S Miyoshi S Ooike K Iwata H Hikawa K Sugaraha International Patent No. PCT\/JP2008\/073864 (WO\/2009\/084693). 2009)."},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1038\/nature09589","article-title":"Suppression of inflammation by a synthetic histone mimic","volume":"468","author":"Nicodeme E","year":"2010","unstructured":"E Nicodeme, et al., Suppression of inflammation by a synthetic histone mimic. Nature 468, 1119\u20131123 (2010).","journal-title":"Nature"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1038\/nature09504","article-title":"Selective inhibition of BET bromodomains","volume":"468","author":"Filippakopoulos P","year":"2010","unstructured":"P Filippakopoulos, et al., Selective inhibition of BET bromodomains. Nature 468, 1067\u20131073 (2010).","journal-title":"Nature"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.cancergencyto.2010.06.007","article-title":"NUT midline carcinoma","volume":"203","author":"French CA","year":"2010","unstructured":"CA French, NUT midline carcinoma. Cancer Genet Cytogenet 203, 16\u201320 (2010).","journal-title":"Cancer Genet Cytogenet"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nrd2781","article-title":"Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls","volume":"8","author":"Baud V","year":"2009","unstructured":"V Baud, M Karin, Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov 8, 33\u201340 (2009).","journal-title":"Nat Rev Drug Discov"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/nature07064","article-title":"IRF4 addiction in multiple myeloma","volume":"454","author":"Shaffer AL","year":"2008","unstructured":"AL Shaffer, et al., IRF4 addiction in multiple myeloma. Nature 454, 226\u2013231 (2008).","journal-title":"Nature"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1093\/jncimonographs\/lgn011","article-title":"Characterization of MYC translocations in multiple myeloma cell lines","author":"Dib A","year":"2008","unstructured":"A Dib, A Gabrea, OK Glebov, PL Bergsagel, WM Kuehl, Characterization of MYC translocations in multiple myeloma cell lines. J Natl Cancer Inst Monogr, pp. 25\u201331 (2008).","journal-title":"J Natl Cancer Inst Monogr"},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian A","year":"2005","unstructured":"A Subramanian, et al., Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102, 15545\u201315550 (2005).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/ng1180","article-title":"PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","author":"Mootha VK","year":"2003","unstructured":"VK Mootha, et al., PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34, 267\u2013273 (2003).","journal-title":"Nat Genet"},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"5595","DOI":"10.1038\/sj.onc.1204595","article-title":"Translocations involving c-myc and c-myc function","volume":"20","author":"Boxer LM","year":"2001","unstructured":"LM Boxer, CV Dang, Translocations involving c-myc and c-myc function. Oncogene 20, 5595\u20135610 (2001).","journal-title":"Oncogene"},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/S1097-2765(02)00633-0","article-title":"Negative regulation of the mammalian UV response by Myc through association with Miz-1","volume":"10","author":"Herold S","year":"2002","unstructured":"S Herold, et al., Negative regulation of the mammalian UV response by Myc through association with Miz-1. Mol Cell 10, 509\u2013521 (2002).","journal-title":"Mol Cell"},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/nature01119","article-title":"Myc suppression of the p21(Cip1) Cdk inhibitor influences the outcome of the p53 response to DNA damage","volume":"419","author":"Seoane J","year":"2002","unstructured":"J Seoane, HV Le, J Massagu\u00e9, Myc suppression of the p21(Cip1) Cdk inhibitor influences the outcome of the p53 response to DNA damage. Nature 419, 729\u2013734 (2002).","journal-title":"Nature"},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1158\/1078-0432.CCR-07-1006","article-title":"A novel Raji-Burkitt's lymphoma model for preclinical and mechanistic evaluation of CD52-targeted immunotherapeutic agents","volume":"14","author":"Lapalombella R","year":"2008","unstructured":"R Lapalombella, et al., A novel Raji-Burkitt's lymphoma model for preclinical and mechanistic evaluation of CD52-targeted immunotherapeutic agents. Clin Cancer Res 14, 569\u2013578 (2008).","journal-title":"Clin Cancer Res"},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.semcancer.2006.07.015","article-title":"The Myc oncoprotein as a therapeutic target for human cancer","volume":"16","author":"Vita M","year":"2006","unstructured":"M Vita, M Henriksson, The Myc oncoprotein as a therapeutic target for human cancer. 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Proc Natl Acad Sci USA 107, 3698\u20133703 (2010).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"2755","DOI":"10.1101\/gad.1712408","article-title":"Myc's broad reach","volume":"22","author":"Eilers M","year":"2008","unstructured":"M Eilers, RN Eisenman, Myc's broad reach. Genes Dev 22, 2755\u20132766 (2008).","journal-title":"Genes Dev"},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0065-230X(10)07006-5","article-title":"MYC in oncogenesis and as a target for cancer therapies","volume":"107","author":"Albihn A","year":"2010","unstructured":"A Albihn, JI Johnsen, MA Henriksson, MYC in oncogenesis and as a target for cancer therapies. Adv Cancer Res 107, 163\u2013224 (2010).","journal-title":"Adv Cancer Res"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1108190108","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T03:58:53Z","timestamp":1654574333000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1108190108"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,9,26]]},"references-count":23,"journal-issue":{"issue":"40","published-print":{"date-parts":[[2011,10,4]]}},"alternative-id":["10.1073\/pnas.1108190108"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1108190108","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.13350957.14722055","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,9,26]]},"assertion":[{"value":"2011-09-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}