Cereblon modulator iberdomide induces degradation of the transcription factors Ikaros and Aiolos: immunomodulation in healthy volunteers and relevance to systemic lupus erythematosus

Schäfer, Peter; Ye, Ying; Wu, Lang; Kosek, Jolanta; Ringheim, Garth E.; Yang, Zhihong; Liu, Liangang; Thomas, Michael A.; Palmisano, Maria; Chopra, Rajesh

doi:10.1136/annrheumdis-2017-212916

Cited by 66 publications

(72 citation statements)

References 24 publications

(14 reference statements)

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“…Given that UBE2G1 inactivation conferred resistance to all CMs tested and also to cereblon-based PROTACs, patient stratification approaches based on UBE2G1 status might be applicable to the development of IMiD drugs and other novel cereblon modulating agents for a variety of human diseases. Lastly, CC-220, a novel CM that targets IKZF1 and IKZF3 for degradation much more effectively than does LEN or POM, retained strong antitumor activity at clinically achievable concentrations ( Schafer et al, 2018 ) in UBE2G1-deficient myeloma cells, suggesting that human patients with resistance to CM drugs owing to diminished UBE2G1 function may be responsive to next-generation CMs that possess higher efficiency and/or potency for degrading the same target protein.…”

Section: Discussionmentioning

confidence: 99%

“…All three IMiD drugs promote the degradation of two hematopoietic transcription factors IKZF1 and IKZF3 to achieve anti-myeloma activity ( Krönke et al, 2014 ) ( Lu et al, 2014a ) ( Gandhi et al, 2014 ), whereas only LEN targets CK1α for effective degradation ( Krönke et al, 2015 ), which is presumably linked to its efficacy in myelodysplastic syndrome with chromosome 5q deletion. CC-220 is a significantly more potent IKZF1 and IKZF3 degrader than IMiD drugs ( Matyskiela et al, 2018 ) ( Nakayama et al, 2017 ) ( Schafer et al, 2018 ), and it is currently in clinical trials for relapsed/refractory multiple myeloma and systemic lupus erythematosus. By contrast, CC-885 is the only aforementioned cereblon modulating agent that allows cereblon to recognize translation termination factor GSPT1 for ubiquitination and degradation ( Matyskiela et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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UBE2G1 governs the destruction of cereblon neomorphic substrates

Lü¹,

Weng²,

Matyskiela³

et al. 2018

eLife

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The cereblon modulating agents (CMs) including lenalidomide, pomalidomide and CC-220 repurpose the Cul4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase complex to induce the degradation of specific neomorphic substrates via polyubiquitination in conjunction with E2 ubiquitin-conjugating enzymes, which have until now remained elusive. Here we show that the ubiquitin-conjugating enzymes UBE2G1 and UBE2D3 cooperatively promote the K48-linked polyubiquitination of CRL4CRBN neomorphic substrates via a sequential ubiquitination mechanism. Blockade of UBE2G1 diminishes the ubiquitination and degradation of neomorphic substrates, and consequent antitumor activities elicited by all tested CMs. For example, UBE2G1 inactivation significantly attenuated the degradation of myeloma survival factors IKZF1 and IKZF3 induced by lenalidomide and pomalidomide, hence conferring drug resistance. UBE2G1-deficient myeloma cells, however, remained sensitive to a more potent IKZF1/3 degrader CC-220. Collectively, it will be of fundamental interest to explore if loss of UBE2G1 activity is linked to clinical resistance to drugs that hijack the CRL4CRBN to eliminate disease-driving proteins.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

UBE2G1 governs the destruction of cereblon neomorphic substrates

Lü¹,

Weng²,

Matyskiela³

et al. 2018

eLife

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“…THAL, LEN and POM promote the degradation of two hematopoietic transcription factors IKZF1 and IKZF3 to achieve anti-myeloma activity (Kronke et al, 2014) (Lu et al, 2014a) (Gandhi et al, 2014), whereas only LEN targets CK1α for effective degradation (Kronke et al, 2015), which is presumably linked to its efficacy in myelodysplastic syndrome with chromosome 5q deletion. CC-220 is a significantly more potent IKZF1 and IKZF3 degrader than IMiD drugs (Matyskiela et al, 2018) (Nakayama et al, 2017) (Schafer et al, 2018), and it is currently in clinical trials for relapsed/refractory multiple myeloma and systemic lupus erythematosus. By contrast, CC-885 is the only aforementioned cereblon modulating agent that allows cereblon to recognize translation termination factor GSPT1 for ubiquitination and degradation (Matyskiela et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

UBE2G1 Governs the Destruction of Cereblon Neomorphic Substrates

Lü¹,

Weng²,

Matyskiela³

et al. 2018

Preprint

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20The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide as well as 21 the novel cereblon modulating agents (CMs) including CC-122, CC-220 and cereblon-based 22 proteolysis-targeting chimaeras (PROTACs) repurpose the Cul4-RBX1-DDB1-CRBN 23 (CRL4 CRBN ) E3 ubiquitin ligase complex to induce the degradation of specific neomorphic 24 substrates via polyubiquitination in conjunction with an E1 ubiquitin-activating enzyme and E2 25 ubiquitin-conjugating enzymes, which have until now remained elusive. Here we show that the 26 ubiquitin-conjugating enzymes UBE2G1 and UBE2D3 cooperatively promote the 27 polyubiquitination of CRL4 CRBN neomorphic substrates in a cereblon-and CM-dependent 28 manner via a sequential ubiquitination mechanism: UBE2D3 transforms the neomorphic 29 substrates into mono-ubiquitinated forms, upon which UBE2G1 catalyzes K48-linked 30 polyubiquitin chain extension. Blockade of UBE2G1 diminishes the ubiquitination and 31 degradation of neomorphic substrates, and consequent antitumor activities elicited by all tested 32CMs. For example, UBE2G1 inactivation significantly attenuated the degradation of myeloma 33 survival factors IKZF1 and IKZF3 induced by lenalidomide and pomalidomide, hence conferring 34 drug resistance. UBE2G1-deficient myeloma cells, however, remained sensitive to a more potent 35 IKZF1/3 degrader CC-220. Collectively, these findings suggest that loss of UBE2G1 activity 36 might be a resistance mechanism to drugs that hijack the CRL4 CRBN to eliminate disease-driving 37 proteins, and that this resistance mechanism can be overcome by next-generation CMs that 38 destroy the same targeted protein more effectively. 39 40 41 42The ubiquitin-proteasome system (UPS) is a highly regulated component of the protein 43 homeostasis network that dictates multiple cellular processes in eukaryotes (Hershko and 44 Ciechanover, 1998). Through the orchestrated actions of ubiquitin-activating enzymes (E1), 45 ubiquitin-conjugating enzymes (E2) and ubiquitin-ligating enzymes (E3), the ε-amine of a lysine 46 residue in a target protein is covalently conjugated with K48-or K11-linked poly-ubiquitin 47 chains, thereby marking the target protein for proteasomal degradation (Jin et al., 2008; 48 Komander and Rape, 2012; Pickart, 2001). Recently, repurposing the Cullin-Ring E3 ligase 49 complexes CRL4 CRBN (Cul4-RBX1-DDB1-CRBN) and CRL2 VHL (Cul2-RBX1-EloB/C-VHL) 50 with small-molecule degraders to remove disease-driving proteins otherwise considered 51 'undruggable' has emerged as a novel therapeutic modality that has the potential to transform 52 drug discovery and development (Bondeson and Crews, 2017; Huang and Dixit, 2016; Lebraud 53 and Heightman, 2017). 54There are two types of small-molecule degraders that have been exploited used to date. The first 55 is represented by thalidomide (THAL), lenalidomide (LEN) and pomalidome (POM), as well as 56 other cereblon modulating agents This class of molecule docks 57 into a tri-tryptophan pocket in the thalidomide...

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“…Consistently, CC-220 administration causes the degradation of IKZF1 and IKZF3 in B cells, T cells and monocytes. In addition, CC-220 inhibited the production of anti-dsDNA and anti-phospholipid autoantibodies in cultured peripheral blood mononuclear cells (PBMCs) from SLE patients [49]. Thus, this study demonstrated the tolerated safety and pharmacodynamic activity of CC-220, indicating its promising clinical development for SLE.…”

Section: Cc-220 (Iberdomide)mentioning

confidence: 60%

“…Recently, a double-blinded, placebo-controlled, single dose-escalation phase 1 study (NCT01733875) has been carried out in healthy volunteers to evaluate safety, pharmacokinetics and pharmacodynamics of CC-220. In the latest report, 56 healthy volunteers were enrolled and randomized into 7 cohorts [49]. In each cohort, six subjects took a single dose of 0.03 to 6 mg CC-220 and two subjects received placebo orally.…”

Section: Cc-220 (Iberdomide)mentioning

confidence: 99%

Novel immunomodulatory drugs and neo-substrates

2020

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Thalidomide, lenalidomide and pomalidomide are immunomodulatory drugs (IMiDs) effective in the treatment of multiple myeloma, myelodysplastic syndrome (MDS) with deletion of chromosome 5q and other hematological malignancies. Recent studies showed that IMiDs bind to CRBN, a substrate receptor of CRL4 E3 ligase, to induce the ubiquitination and degradation of IKZF1 and IKZF3 in multiple myeloma cells, contributing to their anti-myeloma activity. Similarly, lenalidomide exerts therapeutic efficacy via inducing ubiquitination and degradation of CK1α in MDS with deletion of chromosome 5q. Recently, novel thalidomide analogs have been designed for better clinical efficacy, including CC-122, CC-220 and CC-885. Moreover, a number of neo-substrates of IMiDs have been discovered. Proteolysis-targeting chimeras (PROTACs) as a class of bi-functional molecules are increasingly used as a strategy to target otherwise intractable cellular protein. PROTACs appear to have broad implications for novel therapeutics. In this review, we summarized new generation of immunomodulatory compounds, their potential neo-substrates, and new strategies for the design of novel PROTAC drugs.

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Cereblon modulator iberdomide induces degradation of the transcription factors Ikaros and Aiolos: immunomodulation in healthy volunteers and relevance to systemic lupus erythematosus

Cited by 66 publications

References 24 publications

UBE2G1 governs the destruction of cereblon neomorphic substrates

UBE2G1 governs the destruction of cereblon neomorphic substrates

UBE2G1 Governs the Destruction of Cereblon Neomorphic Substrates

Novel immunomodulatory drugs and neo-substrates

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