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 |
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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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•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 & 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</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 & 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 & 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 & inhibitors</subject><subject>Ubiquitination - drug effects</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kTlPAzEQhS0EgnD0VMglRRZ87GFTIKEoHBISDdSW1zsJBu862LuR-Pc4BAIUVJbnvfk844fQMSVnlAp2XjvvmzNGGCFElFW5hUa0YCIjqbKNRqlaZrms6B7aj_GFEJpzVuyiPc6prCQrRqidTDKZfHKMNe78Ehw2ECCBOzzl2Nm5joBb3wxO9z6Mca_DHPqItRn6JLyD87bBDoZXaK3GtdNxpXa_arGHNlGdi4doZ6ZdhKOv8wA9XU8fJ7fZ_cPN3eTqPjM5E2lkoLxmvCxKURhjhGgKWjUmlzQnjHOAWVJmFYHKGKalSVtVguu6SJcS6pIfoMs1dzHULTQGuj5opxbBtjq8K6-t-qt09lnN_VIJRgsqWQKcfgGCfxsg9qq1cbWC7sAPUbG8pFxSwfNkJWurCT7GALPNM5SoVUrqMyX1k1JqOfk93qbhO5ZkuFgbIH3S0kJQ0VjoDDQ2gOlV4-3_9A9nDaIJ</recordid><startdate>20210204</startdate><enddate>20210204</enddate><creator>Surka, Christine</creator><creator>Jin, Liqing</creator><creator>Mbong, Nathan</creator><creator>Lu, Chin-Chun</creator><creator>Jang, In Sock</creator><creator>Rychak, Emily</creator><creator>Mendy, Derek</creator><creator>Clayton, Thomas</creator><creator>Tindall, Elizabeth</creator><creator>Hsu, Christy</creator><creator>Fontanillo, Celia</creator><creator>Tran, Eileen</creator><creator>Contreras, Adrian</creator><creator>Ng, Stanley W.K.</creator><creator>Matyskiela, Mary</creator><creator>Wang, Kai</creator><creator>Chamberlain, Philip</creator><creator>Cathers, Brian</creator><creator>Carmichael, James</creator><creator>Hansen, Joshua</creator><creator>Wang, Jean C.Y.</creator><creator>Minden, Mark D.</creator><creator>Fan, Jinhong</creator><creator>Pierce, Daniel W.</creator><creator>Pourdehnad, Michael</creator><creator>Rolfe, Mark</creator><creator>Lopez-Girona, Antonia</creator><creator>Dick, John E.</creator><creator>Lu, Gang</creator><general>Elsevier Inc</general><general>American Society of Hematology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><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></search><sort><creationdate>20210204</creationdate><title>CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells</title><author>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</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 - 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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> |
fulltext | fulltext |
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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