FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3100577837> ?p ?o ?g. }

• W3100577837 endingPage "677" @default.
• W3100577837 startingPage "661" @default.
• W3100577837 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)." @default.
• W3100577837 created "2020-11-23" @default.
• W3100577837 creator A5001348841 @default.
• W3100577837 creator A5002131259 @default.
• W3100577837 creator A5005430701 @default.
• W3100577837 creator A5005830512 @default.
• W3100577837 creator A5008166711 @default.
• W3100577837 creator A5008777117 @default.
• W3100577837 creator A5014267088 @default.
• W3100577837 creator A5026397928 @default.
• W3100577837 creator A5032115444 @default.
• W3100577837 creator A5035409446 @default.
• W3100577837 creator A5036283039 @default.
• W3100577837 creator A5037376307 @default.
• W3100577837 creator A5041317994 @default.
• W3100577837 creator A5043677242 @default.
• W3100577837 creator A5047862056 @default.
• W3100577837 creator A5048739197 @default.
• W3100577837 creator A5049216661 @default.
• W3100577837 creator A5057444662 @default.
• W3100577837 creator A5059110616 @default.
• W3100577837 creator A5064013294 @default.
• W3100577837 creator A5066043620 @default.
• W3100577837 creator A5068260974 @default.
• W3100577837 creator A5069870180 @default.
• W3100577837 creator A5073531557 @default.
• W3100577837 creator A5076482384 @default.
• W3100577837 creator A5081133747 @default.
• W3100577837 creator A5084626843 @default.
• W3100577837 creator A5090356933 @default.
• W3100577837 creator A5091104294 @default.
• W3100577837 date "2021-02-04" @default.
• W3100577837 modified "2023-10-11" @default.
• W3100577837 title "CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells" @default.
• W3100577837 cites W1527383154 @default.
• W3100577837 cites W1597238753 @default.
• W3100577837 cites W1628369270 @default.
• W3100577837 cites W1973999018 @default.
• W3100577837 cites W1983641075 @default.
• W3100577837 cites W1988976358 @default.
• W3100577837 cites W1997952190 @default.
• W3100577837 cites W1999203943 @default.
• W3100577837 cites W2004878973 @default.
• W3100577837 cites W2015345028 @default.
• W3100577837 cites W2025483501 @default.
• W3100577837 cites W2030592839 @default.
• W3100577837 cites W2048385227 @default.
• W3100577837 cites W2068412287 @default.
• W3100577837 cites W2084778320 @default.
• W3100577837 cites W2086006476 @default.
• W3100577837 cites W2092913179 @default.
• W3100577837 cites W2115459005 @default.
• W3100577837 cites W2117291177 @default.
• W3100577837 cites W2118337461 @default.
• W3100577837 cites W2133345237 @default.
• W3100577837 cites W2133986577 @default.
• W3100577837 cites W2143677057 @default.
• W3100577837 cites W2149650548 @default.
• W3100577837 cites W2161413435 @default.
• W3100577837 cites W2166063624 @default.
• W3100577837 cites W2170286787 @default.
• W3100577837 cites W2255229856 @default.
• W3100577837 cites W2261541794 @default.
• W3100577837 cites W2288337573 @default.
• W3100577837 cites W2470671857 @default.
• W3100577837 cites W2473447250 @default.
• W3100577837 cites W2560012305 @default.
• W3100577837 cites W2592110474 @default.
• W3100577837 cites W2606131188 @default.
• W3100577837 cites W2618306819 @default.
• W3100577837 cites W2729371963 @default.
• W3100577837 cites W2730666287 @default.
• W3100577837 cites W2744235867 @default.
• W3100577837 cites W2752652435 @default.
• W3100577837 cites W2806682325 @default.
• W3100577837 cites W2884204281 @default.
• W3100577837 cites W2885735594 @default.
• W3100577837 cites W2886283685 @default.
• W3100577837 cites W2891710607 @default.
• W3100577837 cites W2899147964 @default.
• W3100577837 cites W2899451374 @default.
• W3100577837 cites W2901513907 @default.
• W3100577837 cites W2909346948 @default.
• W3100577837 cites W2920736663 @default.
• W3100577837 cites W2960291242 @default.
• W3100577837 cites W2969906935 @default.
• W3100577837 cites W2974568688 @default.
• W3100577837 cites W2982554531 @default.
• W3100577837 cites W2999421965 @default.
• W3100577837 cites W3004172643 @default.
• W3100577837 cites W3007932435 @default.
• W3100577837 cites W3010457103 @default.
• W3100577837 doi "https://doi.org/10.1182/blood.2020008676" @default.
• W3100577837 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8215192" @default.
• W3100577837 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33197925" @default.
• W3100577837 hasPublicationYear "2021" @default.
• W3100577837 type Work @default.
• W3100577837 sameAs 3100577837 @default.

• next