CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells

A number of clinically validated drugs have been developed by repurposing the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex with molecular glue degraders to eliminate disease-driving proteins. Here, we present the identification of a first-in-class GSPT1-selective cereblon E3 ligase mod...

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Veröffentlicht in:Blood 2021-02, Vol.137 (5), p.661-677
Hauptverfasser: Surka, Christine, Jin, Liqing, Mbong, Nathan, Lu, Chin-Chun, Jang, In Sock, Rychak, Emily, Mendy, Derek, Clayton, Thomas, Tindall, Elizabeth, Hsu, Christy, Fontanillo, Celia, Tran, Eileen, Contreras, Adrian, Ng, Stanley W.K., Matyskiela, Mary, Wang, Kai, Chamberlain, Philip, Cathers, Brian, Carmichael, James, Hansen, Joshua, Wang, Jean C.Y., Minden, Mark D., Fan, Jinhong, Pierce, Daniel W., Pourdehnad, Michael, Rolfe, Mark, Lopez-Girona, Antonia, Dick, John E., Lu, Gang
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container_end_page 677
container_issue 5
container_start_page 661
container_title Blood
container_volume 137
creator Surka, Christine
Jin, Liqing
Mbong, Nathan
Lu, Chin-Chun
Jang, In Sock
Rychak, Emily
Mendy, Derek
Clayton, Thomas
Tindall, Elizabeth
Hsu, Christy
Fontanillo, Celia
Tran, Eileen
Contreras, Adrian
Ng, Stanley W.K.
Matyskiela, Mary
Wang, Kai
Chamberlain, Philip
Cathers, Brian
Carmichael, James
Hansen, Joshua
Wang, Jean C.Y.
Minden, Mark D.
Fan, Jinhong
Pierce, Daniel W.
Pourdehnad, Michael
Rolfe, Mark
Lopez-Girona, Antonia
Dick, John E.
Lu, Gang
description A number of clinically validated drugs have been developed by repurposing the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex with molecular glue degraders to eliminate disease-driving proteins. Here, we present the identification of a first-in-class GSPT1-selective cereblon E3 ligase modulator, CC-90009. Biochemical, structural, and molecular characterization demonstrates that CC-90009 coopts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation. Depletion of GSPT1 by CC-90009 rapidly induces acute myeloid leukemia (AML) apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features. Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, we uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreases the production of full-length cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009. The screen also revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other cereblon modulators. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation. On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSCs, whose elucidation gives insight into further assessment of CC-90009s clinical utility. These trials were registered at www.clinicaltrials.gov as #NCT02848001 and #NCT04336982). •CC-90009 selectively degrades GSPT1, resulting in acute AML apoptosis and elimination of disease-driving LSCs.•The anti-AML activity of CC-90009 is regulated by the ILF2/ILF3 complex, the mTOR pathway, and the integrated stress response pathway. [Display omitted]
doi_str_mv 10.1182/blood.2020008676
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Here, we present the identification of a first-in-class GSPT1-selective cereblon E3 ligase modulator, CC-90009. Biochemical, structural, and molecular characterization demonstrates that CC-90009 coopts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation. Depletion of GSPT1 by CC-90009 rapidly induces acute myeloid leukemia (AML) apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features. Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, we uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreases the production of full-length cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009. The screen also revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other cereblon modulators. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation. On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSCs, whose elucidation gives insight into further assessment of CC-90009s clinical utility. These trials were registered at www.clinicaltrials.gov as #NCT02848001 and #NCT04336982). •CC-90009 selectively degrades GSPT1, resulting in acute AML apoptosis and elimination of disease-driving LSCs.•The anti-AML activity of CC-90009 is regulated by the ILF2/ILF3 complex, the mTOR pathway, and the integrated stress response pathway. [Display omitted]</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood.2020008676</identifier><identifier>PMID: 33197925</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Acetamides - pharmacology ; Acetamides - therapeutic use ; Adaptor Proteins, Signal Transducing - antagonists &amp; inhibitors ; Animals ; Cell Line, Tumor ; CRISPR-Cas Systems ; Humans ; Isoindoles - pharmacology ; Isoindoles - therapeutic use ; Leukemia, Myeloid, Acute - pathology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Models, Molecular ; Molecular Targeted Therapy ; Myeloid Neoplasia ; Neoplasm Proteins - antagonists &amp; inhibitors ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - enzymology ; Nuclear Factor 45 Protein - physiology ; Nuclear Factor 90 Proteins - physiology ; Peptide Termination Factors - metabolism ; Piperidones - pharmacology ; Piperidones - therapeutic use ; Proteasome Endopeptidase Complex - metabolism ; Protein Conformation ; Protein Processing, Post-Translational - drug effects ; Proteolysis ; Small Molecule Libraries ; Stress, Physiological ; TOR Serine-Threonine Kinases - physiology ; U937 Cells ; Ubiquitin-Protein Ligases - antagonists &amp; inhibitors ; Ubiquitination - drug effects ; Xenograft Model Antitumor Assays</subject><ispartof>Blood, 2021-02, Vol.137 (5), p.661-677</ispartof><rights>2021 American Society of Hematology</rights><rights>2021 by The American Society of Hematology.</rights><rights>2021 by The American Society of Hematology 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4286-4e13b2365685ccc88d517dc49140233eef568f70e7cc2a9c432783ab52a96eb63</citedby><cites>FETCH-LOGICAL-c4286-4e13b2365685ccc88d517dc49140233eef568f70e7cc2a9c432783ab52a96eb63</cites><orcidid>0000-0003-0567-3004 ; 0000-0002-4954-3781 ; 0000-0002-2138-1522 ; 0000-0001-7543-3917 ; 0000-0002-9089-8816 ; 0000-0002-6407-7344 ; 0000-0001-5930-3450 ; 0000-0001-8701-930X ; 0000-0002-6363-5922 ; 0000-0002-7285-7885 ; 0000-0002-4881-5247 ; 0000-0002-9527-8317</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33197925$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Surka, Christine</creatorcontrib><creatorcontrib>Jin, Liqing</creatorcontrib><creatorcontrib>Mbong, Nathan</creatorcontrib><creatorcontrib>Lu, Chin-Chun</creatorcontrib><creatorcontrib>Jang, In Sock</creatorcontrib><creatorcontrib>Rychak, Emily</creatorcontrib><creatorcontrib>Mendy, Derek</creatorcontrib><creatorcontrib>Clayton, Thomas</creatorcontrib><creatorcontrib>Tindall, Elizabeth</creatorcontrib><creatorcontrib>Hsu, Christy</creatorcontrib><creatorcontrib>Fontanillo, Celia</creatorcontrib><creatorcontrib>Tran, Eileen</creatorcontrib><creatorcontrib>Contreras, Adrian</creatorcontrib><creatorcontrib>Ng, Stanley W.K.</creatorcontrib><creatorcontrib>Matyskiela, Mary</creatorcontrib><creatorcontrib>Wang, Kai</creatorcontrib><creatorcontrib>Chamberlain, Philip</creatorcontrib><creatorcontrib>Cathers, Brian</creatorcontrib><creatorcontrib>Carmichael, James</creatorcontrib><creatorcontrib>Hansen, Joshua</creatorcontrib><creatorcontrib>Wang, Jean C.Y.</creatorcontrib><creatorcontrib>Minden, Mark D.</creatorcontrib><creatorcontrib>Fan, Jinhong</creatorcontrib><creatorcontrib>Pierce, Daniel W.</creatorcontrib><creatorcontrib>Pourdehnad, Michael</creatorcontrib><creatorcontrib>Rolfe, Mark</creatorcontrib><creatorcontrib>Lopez-Girona, Antonia</creatorcontrib><creatorcontrib>Dick, John E.</creatorcontrib><creatorcontrib>Lu, Gang</creatorcontrib><title>CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells</title><title>Blood</title><addtitle>Blood</addtitle><description>A number of clinically validated drugs have been developed by repurposing the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex with molecular glue degraders to eliminate disease-driving proteins. Here, we present the identification of a first-in-class GSPT1-selective cereblon E3 ligase modulator, CC-90009. Biochemical, structural, and molecular characterization demonstrates that CC-90009 coopts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation. Depletion of GSPT1 by CC-90009 rapidly induces acute myeloid leukemia (AML) apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features. Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, we uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreases the production of full-length cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009. The screen also revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other cereblon modulators. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation. On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSCs, whose elucidation gives insight into further assessment of CC-90009s clinical utility. These trials were registered at www.clinicaltrials.gov as #NCT02848001 and #NCT04336982). •CC-90009 selectively degrades GSPT1, resulting in acute AML apoptosis and elimination of disease-driving LSCs.•The anti-AML activity of CC-90009 is regulated by the ILF2/ILF3 complex, the mTOR pathway, and the integrated stress response pathway. [Display omitted]</description><subject>Acetamides - pharmacology</subject><subject>Acetamides - therapeutic use</subject><subject>Adaptor Proteins, Signal Transducing - antagonists &amp; inhibitors</subject><subject>Animals</subject><subject>Cell Line, Tumor</subject><subject>CRISPR-Cas Systems</subject><subject>Humans</subject><subject>Isoindoles - pharmacology</subject><subject>Isoindoles - therapeutic use</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Models, Molecular</subject><subject>Molecular Targeted Therapy</subject><subject>Myeloid Neoplasia</subject><subject>Neoplasm Proteins - antagonists &amp; inhibitors</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - enzymology</subject><subject>Nuclear Factor 45 Protein - physiology</subject><subject>Nuclear Factor 90 Proteins - physiology</subject><subject>Peptide Termination Factors - metabolism</subject><subject>Piperidones - pharmacology</subject><subject>Piperidones - therapeutic use</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Protein Conformation</subject><subject>Protein Processing, Post-Translational - drug effects</subject><subject>Proteolysis</subject><subject>Small Molecule Libraries</subject><subject>Stress, Physiological</subject><subject>TOR Serine-Threonine Kinases - physiology</subject><subject>U937 Cells</subject><subject>Ubiquitin-Protein Ligases - antagonists &amp; 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Jin, Liqing ; Mbong, Nathan ; Lu, Chin-Chun ; Jang, In Sock ; Rychak, Emily ; Mendy, Derek ; Clayton, Thomas ; Tindall, Elizabeth ; Hsu, Christy ; Fontanillo, Celia ; Tran, Eileen ; Contreras, Adrian ; Ng, Stanley W.K. ; Matyskiela, Mary ; Wang, Kai ; Chamberlain, Philip ; Cathers, Brian ; Carmichael, James ; Hansen, Joshua ; Wang, Jean C.Y. ; Minden, Mark D. ; Fan, Jinhong ; Pierce, Daniel W. ; Pourdehnad, Michael ; Rolfe, Mark ; Lopez-Girona, Antonia ; Dick, John E. ; Lu, Gang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4286-4e13b2365685ccc88d517dc49140233eef568f70e7cc2a9c432783ab52a96eb63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Acetamides - pharmacology</topic><topic>Acetamides - therapeutic use</topic><topic>Adaptor Proteins, Signal Transducing - antagonists &amp; inhibitors</topic><topic>Animals</topic><topic>Cell Line, Tumor</topic><topic>CRISPR-Cas Systems</topic><topic>Humans</topic><topic>Isoindoles - pharmacology</topic><topic>Isoindoles - therapeutic use</topic><topic>Leukemia, Myeloid, Acute - pathology</topic><topic>Mice</topic><topic>Mice, Inbred NOD</topic><topic>Mice, SCID</topic><topic>Models, Molecular</topic><topic>Molecular Targeted Therapy</topic><topic>Myeloid Neoplasia</topic><topic>Neoplasm Proteins - antagonists &amp; inhibitors</topic><topic>Neoplastic Stem Cells - drug effects</topic><topic>Neoplastic Stem Cells - enzymology</topic><topic>Nuclear Factor 45 Protein - physiology</topic><topic>Nuclear Factor 90 Proteins - physiology</topic><topic>Peptide Termination Factors - metabolism</topic><topic>Piperidones - pharmacology</topic><topic>Piperidones - therapeutic use</topic><topic>Proteasome Endopeptidase Complex - metabolism</topic><topic>Protein Conformation</topic><topic>Protein Processing, Post-Translational - drug effects</topic><topic>Proteolysis</topic><topic>Small Molecule Libraries</topic><topic>Stress, Physiological</topic><topic>TOR Serine-Threonine Kinases - physiology</topic><topic>U937 Cells</topic><topic>Ubiquitin-Protein Ligases - antagonists &amp; inhibitors</topic><topic>Ubiquitination - drug effects</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Surka, Christine</creatorcontrib><creatorcontrib>Jin, Liqing</creatorcontrib><creatorcontrib>Mbong, Nathan</creatorcontrib><creatorcontrib>Lu, Chin-Chun</creatorcontrib><creatorcontrib>Jang, In Sock</creatorcontrib><creatorcontrib>Rychak, Emily</creatorcontrib><creatorcontrib>Mendy, Derek</creatorcontrib><creatorcontrib>Clayton, Thomas</creatorcontrib><creatorcontrib>Tindall, Elizabeth</creatorcontrib><creatorcontrib>Hsu, Christy</creatorcontrib><creatorcontrib>Fontanillo, Celia</creatorcontrib><creatorcontrib>Tran, Eileen</creatorcontrib><creatorcontrib>Contreras, Adrian</creatorcontrib><creatorcontrib>Ng, Stanley W.K.</creatorcontrib><creatorcontrib>Matyskiela, Mary</creatorcontrib><creatorcontrib>Wang, Kai</creatorcontrib><creatorcontrib>Chamberlain, Philip</creatorcontrib><creatorcontrib>Cathers, Brian</creatorcontrib><creatorcontrib>Carmichael, James</creatorcontrib><creatorcontrib>Hansen, Joshua</creatorcontrib><creatorcontrib>Wang, Jean C.Y.</creatorcontrib><creatorcontrib>Minden, Mark D.</creatorcontrib><creatorcontrib>Fan, Jinhong</creatorcontrib><creatorcontrib>Pierce, Daniel W.</creatorcontrib><creatorcontrib>Pourdehnad, Michael</creatorcontrib><creatorcontrib>Rolfe, Mark</creatorcontrib><creatorcontrib>Lopez-Girona, Antonia</creatorcontrib><creatorcontrib>Dick, John E.</creatorcontrib><creatorcontrib>Lu, Gang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Surka, Christine</au><au>Jin, Liqing</au><au>Mbong, Nathan</au><au>Lu, Chin-Chun</au><au>Jang, In Sock</au><au>Rychak, Emily</au><au>Mendy, Derek</au><au>Clayton, Thomas</au><au>Tindall, Elizabeth</au><au>Hsu, Christy</au><au>Fontanillo, Celia</au><au>Tran, Eileen</au><au>Contreras, Adrian</au><au>Ng, Stanley W.K.</au><au>Matyskiela, Mary</au><au>Wang, Kai</au><au>Chamberlain, Philip</au><au>Cathers, Brian</au><au>Carmichael, James</au><au>Hansen, Joshua</au><au>Wang, Jean C.Y.</au><au>Minden, Mark D.</au><au>Fan, Jinhong</au><au>Pierce, Daniel W.</au><au>Pourdehnad, Michael</au><au>Rolfe, Mark</au><au>Lopez-Girona, Antonia</au><au>Dick, John E.</au><au>Lu, Gang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2021-02-04</date><risdate>2021</risdate><volume>137</volume><issue>5</issue><spage>661</spage><epage>677</epage><pages>661-677</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>A number of clinically validated drugs have been developed by repurposing the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex with molecular glue degraders to eliminate disease-driving proteins. Here, we present the identification of a first-in-class GSPT1-selective cereblon E3 ligase modulator, CC-90009. Biochemical, structural, and molecular characterization demonstrates that CC-90009 coopts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation. Depletion of GSPT1 by CC-90009 rapidly induces acute myeloid leukemia (AML) apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features. Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, we uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreases the production of full-length cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009. The screen also revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other cereblon modulators. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation. On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSCs, whose elucidation gives insight into further assessment of CC-90009s clinical utility. These trials were registered at www.clinicaltrials.gov as #NCT02848001 and #NCT04336982). •CC-90009 selectively degrades GSPT1, resulting in acute AML apoptosis and elimination of disease-driving LSCs.•The anti-AML activity of CC-90009 is regulated by the ILF2/ILF3 complex, the mTOR pathway, and the integrated stress response pathway. [Display omitted]</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>33197925</pmid><doi>10.1182/blood.2020008676</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0003-0567-3004</orcidid><orcidid>https://orcid.org/0000-0002-4954-3781</orcidid><orcidid>https://orcid.org/0000-0002-2138-1522</orcidid><orcidid>https://orcid.org/0000-0001-7543-3917</orcidid><orcidid>https://orcid.org/0000-0002-9089-8816</orcidid><orcidid>https://orcid.org/0000-0002-6407-7344</orcidid><orcidid>https://orcid.org/0000-0001-5930-3450</orcidid><orcidid>https://orcid.org/0000-0001-8701-930X</orcidid><orcidid>https://orcid.org/0000-0002-6363-5922</orcidid><orcidid>https://orcid.org/0000-0002-7285-7885</orcidid><orcidid>https://orcid.org/0000-0002-4881-5247</orcidid><orcidid>https://orcid.org/0000-0002-9527-8317</orcidid><oa>free_for_read</oa></addata></record>
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identifier ISSN: 0006-4971
ispartof Blood, 2021-02, Vol.137 (5), p.661-677
issn 0006-4971
1528-0020
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8215192
source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection
subjects Acetamides - pharmacology
Acetamides - therapeutic use
Adaptor Proteins, Signal Transducing - antagonists & inhibitors
Animals
Cell Line, Tumor
CRISPR-Cas Systems
Humans
Isoindoles - pharmacology
Isoindoles - therapeutic use
Leukemia, Myeloid, Acute - pathology
Mice
Mice, Inbred NOD
Mice, SCID
Models, Molecular
Molecular Targeted Therapy
Myeloid Neoplasia
Neoplasm Proteins - antagonists & inhibitors
Neoplastic Stem Cells - drug effects
Neoplastic Stem Cells - enzymology
Nuclear Factor 45 Protein - physiology
Nuclear Factor 90 Proteins - physiology
Peptide Termination Factors - metabolism
Piperidones - pharmacology
Piperidones - therapeutic use
Proteasome Endopeptidase Complex - metabolism
Protein Conformation
Protein Processing, Post-Translational - drug effects
Proteolysis
Small Molecule Libraries
Stress, Physiological
TOR Serine-Threonine Kinases - physiology
U937 Cells
Ubiquitin-Protein Ligases - antagonists & inhibitors
Ubiquitination - drug effects
Xenograft Model Antitumor Assays
title CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells
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