Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells
The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar...
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| creator | Saenz, D T Fiskus, W Qian, Y Manshouri, T Rajapakshe, K Raina, K Coleman, K G Crew, A P Shen, A Mill, C P Sun, B Qiu, P Kadia, T M Pemmaraju, N DiNardo, C Kim, M-S Nowak, A J Coarfa, C Crews, C M Verstovsek, S Bhalla, K N |
| description | The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reverse Phase Protein Array and mass cytometry ‘CyTOF’ analyses demonstrated that ARV-825 caused greater perturbations in messenger RNA (mRNA) and protein expressions than OTX015 in sAML cells. Specifically, compared with OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, p-STAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared with OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the
in vitro
generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the
in vivo
testing of the BRD4-PROTAC based combinations against post-MPN sAML. |
| doi_str_mv | 10.1038/leu.2016.393 |
| format | Article |
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in vitro
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in vivo
testing of the BRD4-PROTAC based combinations against post-MPN sAML.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/leu.2016.393</identifier><identifier>PMID: 28042144</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/1 ; 13/106 ; 13/2 ; 13/31 ; 14 ; 14/1 ; 14/19 ; 14/34 ; 38 ; 38/91 ; 59/5 ; 631/67/1059/602 ; 631/80/82/23 ; 64 ; 64/60 ; 82/79 ; 96 ; 96/2 ; Acute myeloid leukemia ; Animals ; Antigens, CD34 ; Apoptosis ; Apoptosis - drug effects ; Azepines - pharmacology ; Azepines - therapeutic use ; Bcl protein ; Bcl-x protein ; Bet protein ; Biocompatibility ; Biomedical materials ; c-Myc protein ; Cancer Research ; CD34 antigen ; Cell Cycle Proteins ; Cell Line, Tumor ; Cells (biology) ; Critical Care Medicine ; Cyclin-dependent kinase 4 ; Cytometry ; Degradation ; Depletion ; Hematology ; Hematopoietic stem cells ; Humans ; In vitro methods and tests ; In vivo methods and tests ; Inhibitors ; Intensive ; Internal Medicine ; Janus kinase 2 ; Leukemia ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - pathology ; Medicine ; Medicine & Public Health ; Mice ; mRNA ; Myc protein ; Myeloproliferative Disorders - pathology ; Nitriles ; Nuclear Proteins - metabolism ; Oncology ; original-article ; Perturbation ; Progenitor cells ; Protein arrays ; Proteins ; Proteolysis ; Pyrazoles - pharmacology ; Pyrimidines ; Ribonucleic acid ; RNA ; Stat3 protein ; Surgical implants ; Thalidomide - analogs & derivatives ; Thalidomide - pharmacology ; Thalidomide - therapeutic use ; Transcription Factors - metabolism ; Tumor Burden - drug effects ; Ubiquitin ; Ubiquitin-protein ligase ; Ubiquitin-Protein Ligases - metabolism</subject><ispartof>Leukemia, 2017-09, Vol.31 (9), p.1951-1961</ispartof><rights>Macmillan Publishers Limited, part of Springer Nature. 2017</rights><rights>Copyright Nature Publishing Group Sep 2017</rights><rights>Macmillan Publishers Limited, part of Springer Nature. 2017.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c544t-6b42d432c12fb0b9fa52218f6c848bded8c73207a512b94aea4b6ba1c565226e3</citedby><cites>FETCH-LOGICAL-c544t-6b42d432c12fb0b9fa52218f6c848bded8c73207a512b94aea4b6ba1c565226e3</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/leu.2016.393$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/leu.2016.393$$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/28042144$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Saenz, D T</creatorcontrib><creatorcontrib>Fiskus, W</creatorcontrib><creatorcontrib>Qian, Y</creatorcontrib><creatorcontrib>Manshouri, T</creatorcontrib><creatorcontrib>Rajapakshe, K</creatorcontrib><creatorcontrib>Raina, K</creatorcontrib><creatorcontrib>Coleman, K G</creatorcontrib><creatorcontrib>Crew, A P</creatorcontrib><creatorcontrib>Shen, A</creatorcontrib><creatorcontrib>Mill, C P</creatorcontrib><creatorcontrib>Sun, B</creatorcontrib><creatorcontrib>Qiu, P</creatorcontrib><creatorcontrib>Kadia, T M</creatorcontrib><creatorcontrib>Pemmaraju, N</creatorcontrib><creatorcontrib>DiNardo, C</creatorcontrib><creatorcontrib>Kim, M-S</creatorcontrib><creatorcontrib>Nowak, A J</creatorcontrib><creatorcontrib>Coarfa, C</creatorcontrib><creatorcontrib>Crews, C M</creatorcontrib><creatorcontrib>Verstovsek, S</creatorcontrib><creatorcontrib>Bhalla, K N</creatorcontrib><title>Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reverse Phase Protein Array and mass cytometry ‘CyTOF’ analyses demonstrated that ARV-825 caused greater perturbations in messenger RNA (mRNA) and protein expressions than OTX015 in sAML cells. Specifically, compared with OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, p-STAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared with OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the
in vitro
generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the
in vivo
testing of the BRD4-PROTAC based combinations against post-MPN sAML.</description><subject>13</subject><subject>13/1</subject><subject>13/106</subject><subject>13/2</subject><subject>13/31</subject><subject>14</subject><subject>14/1</subject><subject>14/19</subject><subject>14/34</subject><subject>38</subject><subject>38/91</subject><subject>59/5</subject><subject>631/67/1059/602</subject><subject>631/80/82/23</subject><subject>64</subject><subject>64/60</subject><subject>82/79</subject><subject>96</subject><subject>96/2</subject><subject>Acute myeloid leukemia</subject><subject>Animals</subject><subject>Antigens, CD34</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Azepines - pharmacology</subject><subject>Azepines - therapeutic use</subject><subject>Bcl protein</subject><subject>Bcl-x protein</subject><subject>Bet protein</subject><subject>Biocompatibility</subject><subject>Biomedical materials</subject><subject>c-Myc 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Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Leukemia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Saenz, D T</au><au>Fiskus, W</au><au>Qian, Y</au><au>Manshouri, T</au><au>Rajapakshe, K</au><au>Raina, K</au><au>Coleman, K G</au><au>Crew, A P</au><au>Shen, A</au><au>Mill, C P</au><au>Sun, B</au><au>Qiu, P</au><au>Kadia, T M</au><au>Pemmaraju, N</au><au>DiNardo, C</au><au>Kim, M-S</au><au>Nowak, A J</au><au>Coarfa, C</au><au>Crews, C M</au><au>Verstovsek, S</au><au>Bhalla, K N</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2017-09-01</date><risdate>2017</risdate><volume>31</volume><issue>9</issue><spage>1951</spage><epage>1961</epage><pages>1951-1961</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reverse Phase Protein Array and mass cytometry ‘CyTOF’ analyses demonstrated that ARV-825 caused greater perturbations in messenger RNA (mRNA) and protein expressions than OTX015 in sAML cells. Specifically, compared with OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, p-STAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared with OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the
in vitro
generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the
in vivo
testing of the BRD4-PROTAC based combinations against post-MPN sAML.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28042144</pmid><doi>10.1038/leu.2016.393</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0887-6924 |
| ispartof | Leukemia, 2017-09, Vol.31 (9), p.1951-1961 |
| issn | 0887-6924 1476-5551 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5537055 |
| source | MEDLINE; Springer Online Journals Complete; Nature Journals Online |
| subjects | 13 13/1 13/106 13/2 13/31 14 14/1 14/19 14/34 38 38/91 59/5 631/67/1059/602 631/80/82/23 64 64/60 82/79 96 96/2 Acute myeloid leukemia Animals Antigens, CD34 Apoptosis Apoptosis - drug effects Azepines - pharmacology Azepines - therapeutic use Bcl protein Bcl-x protein Bet protein Biocompatibility Biomedical materials c-Myc protein Cancer Research CD34 antigen Cell Cycle Proteins Cell Line, Tumor Cells (biology) Critical Care Medicine Cyclin-dependent kinase 4 Cytometry Degradation Depletion Hematology Hematopoietic stem cells Humans In vitro methods and tests In vivo methods and tests Inhibitors Intensive Internal Medicine Janus kinase 2 Leukemia Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - pathology Medicine Medicine & Public Health Mice mRNA Myc protein Myeloproliferative Disorders - pathology Nitriles Nuclear Proteins - metabolism Oncology original-article Perturbation Progenitor cells Protein arrays Proteins Proteolysis Pyrazoles - pharmacology Pyrimidines Ribonucleic acid RNA Stat3 protein Surgical implants Thalidomide - analogs & derivatives Thalidomide - pharmacology Thalidomide - therapeutic use Transcription Factors - metabolism Tumor Burden - drug effects Ubiquitin Ubiquitin-protein ligase Ubiquitin-Protein Ligases - metabolism |
| title | Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells |
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