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Xinmei Liao et al.
Frontiers in oncology, 11, 753119-753119 (2021-11-05)
Suppression of bromodomain and extra terminal (BET) proteins has a bright prospect to treat MYC-driven tumors. Bromodomain containing 4 (BRD4) is one of the BET proteins. ARV-825, consisting of a BRD4 inhibitor conjugated with a cereblon ligand using proteolysis-targeting chimera
Zhiheng Li et al.
Frontiers in oncology, 10, 574525-574525 (2020-12-17)
Neuroblastoma (NB) is one of the most common solid tumors in childhood. To date, targeting MYCN, a well-established driver gene in high-risk neuroblastoma, is still challenging. In recent years, inhibition of bromodomain and extra terminal (BET) proteins shows great potential
Prabha Shrestha et al.
PLoS pathogens, 17(1), e1009091-e1009091 (2021-01-08)
Pomalidomide (Pom) is an immunomodulatory drug that has efficacy against Kaposi's sarcoma, a tumor caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Pom also induces direct cytotoxicity in primary effusion lymphoma (PEL), a B-cell malignancy caused by KSHV, in part through downregulation
Measuring cereblon as a biomarker of response or resistance to lenalidomide and pomalidomide requires use of standardized reagents and understanding of gene complexity.
Gandhi AK, et al.
British Journal of Haematology, 164, 233-244 (2014)
Mikołaj Słabicki et al.
Nature, 585(7824), 293-297 (2020-06-05)
Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation1. Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets2. They are clinically
Microduplications of 3p26.3p26.2 containing CRBN gene in patients with intellectual disability and behavior abnormalities.
Papuc SM, et al.
European Journal of Medical Genetics, 58, 319-323 (2015)
David Millrine et al.
Proceedings of the National Academy of Sciences of the United States of America, 113(38), 10625-10630 (2016-09-08)
Immunomodulatory drugs (IMiDs) are a family of compounds derived from thalidomide. Binding of the IMiD molecule to the Lon protease Cereblon initiates the degradation of substrates via the ubiquitin proteasome pathway. Here, we show that Cereblon forms a complex with
Su Lin Lim et al.
Haematologica, 104(6), 1209-1220 (2019-01-05)
Proteolysis targeting chimeric molecule ARV 825 causes ubiquitination of bromodomains resulting in their efficient degradation by proteasome activity. Bromodomain degradation down-regulates MYC transcription contributing to growth inhibition of various human cancers. We examined the therapeutic potential of ARV 825 against
Shaunna L Beedie et al.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 34(9), 11395-11404 (2020-07-18)
Cereblon (CRBN) is a substrate recruiter element of the E3 cullin 4-RING ubiquitin ligase complex, and a binding target of immunomodulatory agents (IMiDs). CRBN is responsible for the pleiotropic effects of IMiDs, yet its function in angiogenesis and in mediating
Thalidomide-based induction regimens are as effective as bortezomib-based regimens in elderly patients with multiple myeloma with cereblon expression.
Jung SH, et al.
Annals of Hematology, 95, 1645-1651 (2016)
Seung-Joo Yang et al.
Pharmaceuticals (Basel, Switzerland), 14(6) (2021-06-03)
Cereblon (CRBN), a primary target of immune-modulatory imide drugs (IMiDs), functions as a substrate receptor in the CUL4-RBX1-DDB1-CRBN (known as CRL4CRBN) E3 ubiquitin ligase complex. Binding of IMiDs to CRBN redirects the CRL4CRBN E3 ubiquitin ligase to recruit or displace
Dolores Del Prete et al.
The Journal of biological chemistry, 291(33), 17209-17227 (2016-06-22)
The amyloid precursor protein (APP), whose mutations cause Alzheimer disease, plays an important in vivo role and facilitates transmitter release. Because the APP cytosolic region (ACR) is essential for these functions, we have characterized its brain interactome. We found that
Nan Zhou et al.
Leukemia, 33(8), 2006-2021 (2019-02-15)
Ikaros family zinc finger protein 1 and 3 (IKZF1 and IKZF3) are transcription factors that promote multiple myeloma (MM) proliferation. The immunomodulatory imide drug (IMiD) lenalidomide promotes myeloma cell death via Cereblon (CRBN)-dependent ubiquitylation and proteasome-dependent degradation of IKZF1 and
Cereblon inhibits proteasome activity by binding to the 20S core proteasome subunit beta type 4.
Lee KM, et al.
Biochemical and Biophysical Research Communications, 427, 618-618 (2012)
Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity.
Eichner R, et al.
Nature Medicine, 22, 735-735 (2016)
Immunomodulatory drugs target IKZF1-IRF4-MYC axis in primary effusion lymphoma in a cereblon-dependent manner and display synergistic cytotoxicity with BRD4 inhibitors.
Gopalakrishnan R, et al.
Oncogene, 35, 1797-1810 (2016)
Expression of CRBN, IKZF1, and IKZF3 does not predict lenalidomide sensitivity and mutations in the cereblon pathway are infrequent in multiple myeloma
Dimopoulos K, et al.
Leukemia & Lymphoma, 60(1), 180-188 (2019)
Identification of a primary target of thalidomide teratogenicity.
Ito T, et al.
Science, 327, 1345-1350 (2010)
Thang Van Nguyen et al.
Proceedings of the National Academy of Sciences of the United States of America, 114(14), 3565-3571 (2017-03-23)
Glutamine synthetase (GS) plays an essential role in metabolism by catalyzing the synthesis of glutamine from glutamate and ammonia. Our recent study showed that CRBN, a direct protein target for the teratogenic and antitumor activities of immunomodulatory drugs such as
Sara Petillo et al.
Cell death & disease, 12(9), 836-836 (2021-09-06)
Multiple Myeloma (MM) is an incurable hematologic malignancy of terminally differentiated plasma cells (PCs), where immune interactions play a key role in the control of cancer cell growth and survival. In particular, MM is characterized by a highly immunosuppressive bone
Hyunji Moon et al.
Nature communications, 11(1), 5489-5489 (2020-11-01)
Calcium flux regulating intracellular calcium levels is essential and modulated for efficient efferocytosis. However, the molecular mechanism by which calcium flux is modulated during efferocytosis remains elusive. Here, we report that Orai1, a Crbn substrate, is upregulated via its attenuated
Raghu Vannam et al.
Cell chemical biology, 28(4), 503-514 (2021-01-06)
The enhancer factors CREB-binding protein (CBP) and p300 (also known as KAT3A and KAT3B) maintain gene expression programs through lysine acetylation of chromatin and transcriptional regulators and by scaffolding functions mediated by several protein-protein interaction domains. Small molecule inhibitors that
Saeko Kuwahara-Ota et al.
British journal of haematology, 191(5), 784-795 (2020-06-20)
An increase in immunosuppressive myeloid-derived suppressor cells (MDSCs) is associated with disease progression and treatment resistance in multiple myeloma (MM). We investigated the mechanisms underlying MDSC induction, and sought to discover a strategy for prevention of MDSC induction in MM.
Functional modulation of AMP-activated protein kinase by cereblon.
Lee KM, et al.
Biochimica et Biophysica Acta, 1813, 448-448 (2011)
Kidae Kim et al.
Scientific reports, 9(1), 19654-19654 (2019-12-25)
Proteolysis targeting chimeras (PROTACs) are an emerging strategy for promoting targeted protein degradation by inducing the proximity between targeted proteins and E3 ubiquitin ligases. Although successful degradation of numerous proteins by PROTACs has been demonstrated, the elements that determine the
Nicola E A Chessum et al.
Journal of medicinal chemistry, 61(3), 918-933 (2017-12-15)
Demonstrating intracellular protein target engagement is an essential step in the development and progression of new chemical probes and potential small molecule therapeutics. However, this can be particularly challenging for poorly studied and noncatalytic proteins, as robust proximal biomarkers are
Maria Pia Abruzzese et al.
Cell death & disease, 10(4), 324-324 (2019-04-13)
The transcription factor Myeloid Ecotropic Insertion Site 2 (MEIS2) has been identified as a cellular substrate of the E3-ubiquitin ligase complex CRL4-cereblon (CRL4CRBN) in crystal structure and by biochemical screen. Emerging evidence suggests that IMiDs can block MEIS2 from binding
Yuan Xiao Zhu et al.
Blood cancer journal, 9(2), 19-19 (2019-02-12)
To understand immunomodulatory drug (IMiD) resistance in multiple myeloma (MM), we created isogenic human multiple myeloma cell lines (HMCLs) sensitive and resistant to lenalidomide, respectively. Four HMCLs were demonstrated to be resistant to all IMiDs including lenalidomide, pomalidomide, and CC-220
Shuiyan Wu et al.
Cancer cell international, 21(1), 230-230 (2021-04-24)
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a high risk of induction failure and poor outcomes, with relapse due to drug resistance. Recent studies show that bromodomains and extra-terminal (BET) protein inhibitors are promising anti-cancer agents. ARV-825
Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs.
Chamberlain PP, et al.
Nature Structural and Molecular Biology, 21, 803-803 (2014)
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