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Eric S Fischer - One of the best experts on this subject based on the ideXlab platform.
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triple degradation of btk ikzf1 and IKZF3 in b cell malignancies
Blood, 2018Co-Authors: Sara N Morrow, Dennis Dobrovolsky, Eric T Wang, Katherine A Donovan, Tyler B Faust, Guang Yang, Eric S Fischer, Steven P Treon, Radoslaw P Nowak, David M WeinstockAbstract:Abstract Bruton's Tyrosine Kinase (BTK), a TEC-family non-receptor tyrosine kinase, plays a critical role in B-cell development and function. Targeting of BTK with covalent inhibitors like ibrutinib has become a standard approach for many B-cell malignancies, including chronic lymphocytic leukemia (CLL), Waldenstrom macroglobulinemia, mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL). Yet, many patients demonstrate intrinsic or acquired resistance to covalent BTK inhibition. The prognosis of patients who relapse after ibrutinib treatment for MCL or CLL is dismal, highlighting the urgent need for new approaches that overcome resistance to current BTK inhibitors. We hypothesized that degradation of BTK could be a better alternative to inhibition alone, as it would both: 1) maintain efficacy in cells harboring the ibrutinib-resistant BTK C418S mutation and 2) target non-catalytic functions of BTK. To address this, we turned to a small molecule-mediated protein degradation platform that utilizes an E3 ligase-targeting moiety linked to the ligand of a target of interest, so that the target can be marked for ubiquitination and subsequent proteasomal degradation. We previously showed that BTK is one of the most robustly degraded kinase targets using a nonspecific kinase inhibitor linked to a imide-based core followed by agnostic proteomics. We synthesized highly potent and selective degraders of BTK using imides as a base. To do so, the parent BTK inhibitor CGI1746 was linked to thalidomide using either polyethylene glycol (DD-03-007) linkers or saturated hydrocarbon chain (DD-03-171) linkers. After verifying that these degraders induce dimerization of BTK and CRBN and penetrate cells, we explored the pharmacological effects in vitro. Both DD-03-007 and DD-03-171 reduced BTK levels at concentrations as low as 40 nM within 4h of treatment. Furthermore, cellular BTK levels remained low for 24h after washout, showing that these degraders are capable of sustaining depletion of BTK for an extended period of time (Figure). DD-03-007 and DD-03-171 are both ligase and proteasome-dependent, as shown by co-treatment with bortezomib or MLN-4924 as well as competition experiments with lenalidomide or CGI-1746. Moreover, the degraders exhibited strong synergy with the HCK inhibitor A419259, suggesting that it would be possible to recapitulate ibrutinib's previously reported polypharmacology with an HCK inhibitor. We overexpressed wild-type or C481S BTK in TMD-8 cells and ran an antiproliferation assay, which showed that DD-03-007 overcame ibrutinib resistance associated with BTK C481S mutation. Next, we explored the effects of the degraders in MCL specifically. Proteomic analysis showed that DD-03-171 is a triple-degrader, as it degrades BTK but retains degradation activity on IKZF1 and IKZF3. Finally, we performed In vivo efficacy studies in cell line and patient-derived xenograft (PDX) models of MCL. The latter was obtained from a patient who had progressed on ibrutinib. In both models, DD-03-171 caused a significant reduction in tumor burden at an early timepoint. DD-03-171 also markedly extended survival compared to treatment with ibrutinib or lenalidomide alone (Figure). In conclusion, we developed highly potent and selective BTK degraders with activity in vivo against human MCL that induce the degradation of multiple factors essential for MCL survival. Download : Download high-res image (164KB) Download : Download full-size image Disclosures Treon: Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Johnson & Johnson: Consultancy; BMS: Research Funding. Weinstock: Novartis, Dragonfly, Travera, DxTerity, Travera: Consultancy; Novartis: Consultancy, Research Funding; Novartis, Astra Zeneca, Abbvie, Aileron, Surface Oncology, Daiichi Sankyo: Research Funding; Genentech/Roche, Monsanto: Consultancy; Astra Zeneca, JAX, Samumed, Regeneron, Sun Pharma, Prescient: Patents & Royalties; Travera: Equity Ownership. Gray: Syros, Soltego, Petra, C4 Therapeutics: Equity Ownership.
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triple degradation of btk ikzf1 and IKZF3 in b cell malignancies
Blood, 2018Co-Authors: Sara N Morrow, Dennis Dobrovolsky, Eric T Wang, R Nowak, Katherine A Donovan, Tyler B Faust, Guang Yang, Eric S Fischer, Steven P Treon, David M WeinstockAbstract:Bruton9s Tyrosine Kinase (BTK), a TEC-family non-receptor tyrosine kinase, plays a critical role in B-cell development and function. Targeting of BTK with covalent inhibitors like ibrutinib has become a standard approach for many B-cell malignancies, including chronic lymphocytic leukemia (CLL), Waldenstrom macroglobulinemia, mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL). Yet, many patients demonstrate intrinsic or acquired resistance to covalent BTK inhibition. The prognosis of patients who relapse after ibrutinib treatment for MCL or CLL is dismal, highlighting the urgent need for new approaches that overcome resistance to current BTK inhibitors. We hypothesized that degradation of BTK could be a better alternative to inhibition alone, as it would both: 1) maintain efficacy in cells harboring the ibrutinib-resistant BTK C418S mutation and 2) target non-catalytic functions of BTK. To address this, we turned to a small molecule-mediated protein degradation platform that utilizes an E3 ligase-targeting moiety linked to the ligand of a target of interest, so that the target can be marked for ubiquitination and subsequent proteasomal degradation. We previously showed that BTK is one of the most robustly degraded kinase targets using a nonspecific kinase inhibitor linked to a imide-based core followed by agnostic proteomics. We synthesized highly potent and selective degraders of BTK using imides as a base. To do so, the parent BTK inhibitor CGI1746 was linked to thalidomide using either polyethylene glycol (DD-03-007) linkers or saturated hydrocarbon chain (DD-03-171) linkers. After verifying that these degraders induce dimerization of BTK and CRBN and penetrate cells, we explored the pharmacological effects in vitro. Both DD-03-007 and DD-03-171 reduced BTK levels at concentrations as low as 40 nM within 4h of treatment. Furthermore, cellular BTK levels remained low for 24h after washout, showing that these degraders are capable of sustaining depletion of BTK for an extended period of time (Figure). DD-03-007 and DD-03-171 are both ligase and proteasome-dependent, as shown by co-treatment with bortezomib or MLN-4924 as well as competition experiments with lenalidomide or CGI-1746. Moreover, the degraders exhibited strong synergy with the HCK inhibitor A419259, suggesting that it would be possible to recapitulate ibrutinib9s previously reported polypharmacology with an HCK inhibitor. We overexpressed wild-type or C481S BTK in TMD-8 cells and ran an antiproliferation assay, which showed that DD-03-007 overcame ibrutinib resistance associated with BTK C481S mutation. Next, we explored the effects of the degraders in MCL specifically. Proteomic analysis showed that DD-03-171 is a triple-degrader, as it degrades BTK but retains degradation activity on IKZF1 and IKZF3. Finally, we performed In vivo efficacy studies in cell line and patient-derived xenograft (PDX) models of MCL. The latter was obtained from a patient who had progressed on ibrutinib. In both models, DD-03-171 caused a significant reduction in tumor burden at an early timepoint. DD-03-171 also markedly extended survival compared to treatment with ibrutinib or lenalidomide alone (Figure). In conclusion, we developed highly potent and selective BTK degraders with activity in vivo against human MCL that induce the degradation of multiple factors essential for MCL survival. Disclosures Treon:Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Johnson & Johnson: Consultancy; BMS: Research Funding. Weinstock:Novartis, Dragonfly, Travera, DxTerity, Travera: Consultancy; Novartis: Consultancy, Research Funding; Novartis, Astra Zeneca, Abbvie, Aileron, Surface Oncology, Daiichi Sankyo: Research Funding; Genentech/Roche, Monsanto: Consultancy; Astra Zeneca, JAX, Samumed, Regeneron, Sun Pharma, Prescient: Patents & Royalties; Travera: Equity Ownership. Gray:Syros, Soltego, Petra, C4 Therapeutics: Equity Ownership.
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genome wide screen identifies cullin ring ligase machinery required for lenalidomide dependent crl4crbn activity
Blood, 2018Co-Authors: Benjamin L. Ebert, Eric S Fischer, Quinlan L. Sievers, Jessica A Gasser, Glenn S CowleyAbstract:Lenalidomide mediates the ubiquitination and degradation of Ikaros family zinc finger protein 1 (IKZF1), IKZF3, and casein kinase 1α (CK1α) by facilitating their interaction with cereblon (CRBN), the substrate receptor for the CRL4CRBN E3 ubiquitin ligase. Through this mechanism, lenalidomide is a clinically effective treatment of multiple myeloma and myelodysplastic syndrome (MDS) with deletion of chromosome 5q [del(5q) MDS]. To identify the cellular machinery required for lenalidomide-induced CRL4CRBN activity, we performed a positive selection, genome-scale clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) screen in a lenalidomide-sensitive myeloma cell line. CRBN was the top-ranking gene, with all CRBN-targeting guide RNAs (gRNAs) ranking as the 6 highest-scoring gRNAs. A counterscreen using an IKZF3 degron reporter to assay lenalidomide-induced protein degradation highlighted regulators of cullin-RING ligase neddylation and 2 E2 ubiquitin-conjugating enzymes as necessary for efficient lenalidomide-induced protein degradation. We demonstrated that loss of UBE2M or members of the constitutive photomorphogenesis 9 (COP9) signalosome results in altered neddylation of cullin 4A and impairs lenalidomide-dependent CRL4CRBN activity. Additionally, we established that UBE2D3 and UBE2G1 play distinct roles in substrate ubiquitination by CRL4CRBN, with UBE2D3 acting to prime targets via monoubiquitination and UBE2G1 functioning to extend polyubiquitin chains with lysine 48 linkages. The validation of UBE2D3 and UBE2G1 highlights the functional capacity of CRISPR-Cas9 screening to identify E2 ubiquitin-conjugating enzyme and E3 ubiquitin ligase complex pairings. More broadly, these findings establish key proteins required for lenalidomide-dependent CRL4CRBN function in myeloma and inform potential mechanisms of drug resistance.
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psilac mass spectrometry reveals zfp91 as imid dependent substrate of the crl4crbn ubiquitin ligase
Nature Communications, 2017Co-Authors: Charles M Ponthier, Katherine A Donovan, Michael B Stadler, Ragna Sack, Jan Seebacher, Eric S FischerAbstract:Thalidomide and its derivatives lenalidomide and pomalidomide (IMiDs) are effective treatments of haematologic malignancies. It was shown that IMiDs impart gain-of-function properties to the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) ubiquitin ligase that enable binding, ubiquitination and degradation of key therapeutic targets such as IKZF1, IKZF3 and CSNK1A1. While these substrates have been implicated as efficacy targets in multiple myeloma (MM) and 5q deletion associated myelodysplastic syndrome (del(5q)-MDS), other targets likely exist. Using a pulse-chase SILAC mass spectrometry-based proteomics approach, we demonstrate that lenalidomide induces the ubiquitination and degradation of ZFP91. We establish ZFP91 as a bona fide IMiD-dependent CRL4CRBN substrate and further show that ZFP91 harbours a zinc finger (ZnF) motif, related to the IKZF1/3 ZnF, critical for IMiD-dependent CRBN binding. These findings demonstrate that single time point pulse-chase SILAC mass spectrometry-based proteomics (pSILAC MS) is a sensitive approach for target identification of small molecules inducing selective protein degradation.
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structural basis of lenalidomide induced ck1α degradation by the crl4 crbn ubiquitin ligase
Nature, 2016Co-Authors: Eric S Fischer, Georg Petzold, Nicolas H ThomaAbstract:Thalidomide and its derivatives, lenalidomide and pomalidomide, are immune modulatory drugs (IMiDs) used in the treatment of haematologic malignancies. IMiDs bind CRBN, the substrate receptor of the CUL4-RBX1-DDB1-CRBN (also known as CRL4(CRBN)) E3 ubiquitin ligase, and inhibit ubiquitination of endogenous CRL4(CRBN) substrates. Unexpectedly, IMiDs also repurpose the ligase to target new proteins for degradation. Lenalidomide induces degradation of the lymphoid transcription factors Ikaros and Aiolos (also known as IKZF1 and IKZF3), and casein kinase 1α (CK1α), which contributes to its clinical efficacy in the treatment of multiple myeloma and 5q-deletion associated myelodysplastic syndrome (del(5q) MDS), respectively. How lenalidomide alters the specificity of the ligase to degrade these proteins remains elusive. Here we present the 2.45 A crystal structure of DDB1-CRBN bound to lenalidomide and CK1α. CRBN and lenalidomide jointly provide the binding interface for a CK1α β-hairpin-loop located in the kinase N-lobe. We show that CK1α binding to CRL4(CRBN) is strictly dependent on the presence of an IMiD. Binding of IKZF1 to CRBN similarly requires the compound and both, IKZF1 and CK1α, use a related binding mode. Our study provides a mechanistic explanation for the selective efficacy of lenalidomide in del(5q) MDS therapy. We anticipate that high-affinity protein-protein interactions induced by small molecules will provide opportunities for drug development, particularly for targeted protein degradation.
Jing Zheng - One of the best experts on this subject based on the ideXlab platform.
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pan pim kinase inhibitors enhance lenalidomide s anti myeloma activity via cereblon ikzf1 3 cascade
Cancer Letters, 2019Co-Authors: Jing Zheng, Yonggang Sha, Logan Roof, Oded Foreman, John Lazarchick, Jagadish Kummetha Venkta, Cleopatra Kozlowski, Cristina Gasparetto, Nelson J ChaoAbstract:Abstract Multiple myeloma remains an incurable disease, and continued efforts are required to develop novel agents and novel drug combinations with more effective anti-myeloma activity. Here, we show that the pan-PIM kinase inhibitors SGI1776 and CX6258 exhibit significant anti-myeloma activity and that combining a pan-PIM kinase inhibitor with the immunomodulatory agent lenalidomide in an in vivo myeloma xenograft mouse model resulted in synergistic myeloma cell killing without additional hematologic or hepatic toxicities. Further investigations indicated that treatment with a pan-PIM kinase inhibitor promoted increased ubiquitination and subsequent degradation of IKZF1 and IKZF3, two transcription factors crucial for survival of myeloma cells. Combining a pan-PIM kinase inhibitor with lenalidomide led to more effective degradation of IKZF1 and IKZF3 in multiple myeloma cell lines as well as xenografts of myeloma tumors. We also demonstrated that treatment with a pan-PIM kinase inhibitor resulted in increased expression of cereblon, and that knockdown of cereblon via a shRNA lentivirus abolished the effects of PIM kinase inhibition on the degradation of IKZF1 and IKZF3 and myeloma cell apoptosis, demonstrating a central role of cereblon in pan-PIM kinase inhibitor-mediated down-regulation of IKZF1 and IKZF3 and myeloma cell killing. These data elucidate the mechanism of pan-PIM kinase inhibitor mediated anti-myeloma effect and the rationale for the synergy observed with lenalidomide co-treatment, and provide justification for a clinical trial of the combination of pan-PIM kinase inhibitors and lenalidomide for the treatment of multiple myeloma.
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pan pim kinase inhibitors enhance lenalidomide s anti myeloma activity via cereblon ikzf1 3 cascade
Blood, 2017Co-Authors: Yonggang Sha, Jing Zheng, Yubin KangAbstract:Pan-PIM Kinase Inhibitors Enhance Lenalidomide9s Anti-myeloma Activity Via Cereblon-IKZF1/3 Cascade Yonggang Sha1, Jing Zheng2, Jianda Hu2+, and Yubin Kang1+ 1Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA; 2Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, China + Corresponding author: Yubin Kang, MD, Email: yubin.kang@duke.edu; and Jianda Hu, Email: drjiandahu@163.com. ABSTRACT Purpose: Multiple myeloma (MM) remains an incurable disease, and continuous efforts are required to develop novel therapeutic agents and novel drug combinations with more effective anti-myeloma activity. Immunomodulatory agents (IMiDs) including lenalidomide are one of the mainstays in the treatment of MM. It is important to identify and develop novel agents that can work with IMiDs for enhanced anti-myeloma effects. Here, we determined anti-myeloma effect of pan-PIM inhibitors and the synergistic anti-myeloma effects of pan-PIM inhibitors with IMiDs (lenalidomide). Experimental Design: The anti-myeloma activities of pan-PIM inhibitors (SGI1776 and CX6258) and the synergistic anti-myeloma effects of pan-PIM inhibitors with lenalidomide were determined in human myeloma cells, transplanted VK*MYC myeloma mice, and myeloma xenograft mouse models. Western blot, protein stability assay, shRNA specific gene knockdown, and ubiquitination assay were performed to determine the molecular mechanisms involved. Results: Pan-PIM inhibitors (SGI1776 and CX6258) induced the apoptosis of MM cells and exhibited significant anti-myeloma activities in human myeloma cells and in transplanted VK*MYC myeloma mice. Combination of PIM inhibitors with lenalidomide showed synergistic anti-myeloma effects without additional hematological or liver toxicities in vivo in myeloma xenograft mouse models. The treatments of pan-PIM inhibitors promoted ubiquitination and degradation of IKZF1 and IKZF3, the two transcription factors important for the survival of myeloma cells, and combining Pan-PIM inhibitors with lenalidomide leds to more effective degradation of IKZF1 and IKZF3 in vitro in human multiple myeloma cells and in vivo in myeloma xenograft mouse model. We further demonstrated that treatments with pan-PIM inhibitors resulted in an increased expression of Cereblon, and knockdown of Cereblon with shRNA abolished the effects of pan-PIM inhibitors on IKZF1 and IKZF3, demonstrating a central role of Cereblon in Pan-PIM inhibitor-mediated IKZF1/3 degradation. Conclusions: We demonstrated that pan-PIM inhibitors (SGI1776 and CX6258) exhibited significant anti-myeloma activities and combination of pan-PIM inhibitors with lenalidomide showed synergistic anti-myeloma effects without additional hematological or liver toxicities. Mechanistically, pan-PIM kinase inhibitors enhance lenalidomide9s anti-myeloma activity via Cereblon-IKZF1/3 Cascade. Our study provides molecular rationale and justification for clinical trials combining pan-PIM inhibitors and lenalidomide for the treatment of myeloma. Disclosures No relevant conflicts of interest to declare.
Michael B Stadler - One of the best experts on this subject based on the ideXlab platform.
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psilac mass spectrometry reveals zfp91 as imid dependent substrate of the crl4crbn ubiquitin ligase
Nature Communications, 2017Co-Authors: Charles M Ponthier, Katherine A Donovan, Michael B Stadler, Ragna Sack, Jan Seebacher, Eric S FischerAbstract:Thalidomide and its derivatives lenalidomide and pomalidomide (IMiDs) are effective treatments of haematologic malignancies. It was shown that IMiDs impart gain-of-function properties to the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) ubiquitin ligase that enable binding, ubiquitination and degradation of key therapeutic targets such as IKZF1, IKZF3 and CSNK1A1. While these substrates have been implicated as efficacy targets in multiple myeloma (MM) and 5q deletion associated myelodysplastic syndrome (del(5q)-MDS), other targets likely exist. Using a pulse-chase SILAC mass spectrometry-based proteomics approach, we demonstrate that lenalidomide induces the ubiquitination and degradation of ZFP91. We establish ZFP91 as a bona fide IMiD-dependent CRL4CRBN substrate and further show that ZFP91 harbours a zinc finger (ZnF) motif, related to the IKZF1/3 ZnF, critical for IMiD-dependent CRBN binding. These findings demonstrate that single time point pulse-chase SILAC mass spectrometry-based proteomics (pSILAC MS) is a sensitive approach for target identification of small molecules inducing selective protein degradation.
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structure of the ddb1 crbn e3 ubiquitin ligase in complex with thalidomide
Nature, 2014Co-Authors: Eric S Fischer, Kerstin Bohm, John R Lydeard, Haidi Yang, Michael B Stadler, Simone CavadiniAbstract:In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4–RBX1–DDB1–CRBN (known as CRL4CRBN) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4CRBN. Here we present crystal structures of the DDB1–CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4CRBN and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4CRBN. Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4CRBN while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins. The crystal structures of thalidomide and its derivatives bound to the E3 ligase subcomplex DDB1–CRBN are shown; these drugs are found to have dual functions, interfering with the binding of certain cellular substrates to the E3 ligase but promoting the binding of others, thereby modulating the degradation of cellular proteins. Introduced in Europe in 1957 as a mild sedative, thalidomide was widely used in pregnant women as a treatment for morning sickness. This led to the birth of thousands of children with multiple defects and the drug was withdrawn in 1962. Since then thalidomide and its derivatives have emerged as effective treatments for the cancer multiple myeloma and the associated disorder 5q-dysplasia. The primary teratogenic target of thalidomide is cereblon (CRBN), part of E3 ubiquitin ligase complex CUL4–RBX1–DDB1–CRBN (CRL4CRBN). Here, Nicolas Thoma and colleagues present the crystal structure of DDB1–CRBN E3 ubiquitin ligase bound to thalidomide and to the related drugs lenalidomide and pomalidomide. The structure establishes the molecular mechanism underlying CRBN's enantioselective action. Further structure–function analysis reveals that these drugs have dual functions, interfering with the binding of certain cellular substrates to the E3 ligase but promoting the binding of others, thereby modulating the degradation of cellular proteins.
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structure of the ddb1 crbn e3 ubiquitin ligase in complex with thalidomide
Nature, 2014Co-Authors: Eric S Fischer, Kerstin Bohm, John R Lydeard, Haidi Yang, Michael B Stadler, Simone Cavadini, Jane Nagel, Fabrizio C Serluca, Vincent Acker, Gondichatnahalli M LingarajuAbstract:In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4(CRBN). Here we present crystal structures of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4(CRBN) and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4(CRBN). Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4(CRBN) while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins.
Hong Chang - One of the best experts on this subject based on the ideXlab platform.
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ikzf1 3 protein expressions are associated with a better survival in relapsed refractory multiple myeloma patients treated with lenalidomide
Blood, 2016Co-Authors: Maryam Pourabdollah, Mohammad Bahmanyar, Eshetu G. Atenafu, Donna Reece, Hong ChangAbstract:It has been demonstrated that lenalidomide causes selective degradation of IKZF1 (Ikaros) and IKZF3 (Aiolos) which are two essential transcription factors for proliferation of multiple myeloma cells. Consequently, the drug sets up a molecular sequence of events that lead to programmed cell death in the tumoral cells. This anti-proliferative effect is mediated by down-regulation of c-Myc and interferon regulatory factor 4 (IRF4). However, it is not clear whether IKZF1/IKZF3 protein expression in myeloma cells is predictive of clinical outcome. Thus, we evaluated bone marrow samples of 50 relapsed/refractory multiple myeloma (MM) patients regarding IKZF1/3 protein expression before starting lenalidomide. There were 31 males and 19 females with median age of 59 years (range 41-75). They all had received lenalidomide-based therapy after relapse following autologous stem cell transplantation (ASCT), thalidomide, or bortezomib. The median follow-up was 86.4 months. By immunohistochemistry (IHC), CD138 positive myeloma cell aggregates were examined for IKZF1 and IKZF3 protein expression. We used H-score method (range 0-300) based on the intensity and percentage of the stained myeloma cells. Cases were considered positive for IKZF1 or IKZF3 if H-score is equal or over 150 or 200, respectively. IKZF1 showed nuclear staining but IKZF3 showed both nuclear and cytoplasmic staining. IKZF1 and IKZF3 were expressed in 72% and 58% of the bone marrow specimens, respectively. IKZF1 and IKZF3 expressions were strongly correlated (p Our study demonstrates that expressions of the IKZF1/3 proteins detected by IHC are correlated with superior survival outcome in refractory MM patients treated with lenalidomide. IHC is routinely available, robust and inexpensive method. Thus, if confirmed in a larger prospective study, IKZF1/3 immunostaining can be readily adopted in clinical practice for prediction of drug response and clinical outcomes in MM patients receiving lenalidomide therapy. Disclosures Reece:Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.
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high ikzf1 3 protein expression is a favorable prognostic factor for survival of relapsed refractory multiple myeloma patients treated with lenalidomide
Journal of Hematology & Oncology, 2016Co-Authors: Maryam Pourabdollah, Mohammad Bahmanyar, Eshetu G. Atenafu, Donna Reece, Hong Chang, Jian HouAbstract:The aim of this study is to assess nucleoprotein expression of IKZF1/3 in patients with relapsed/refractory multiple myeloma (MM) who received lenalidomide-based therapy and correlated them with their clinical outcomes. A total of 50 patients diagnosed with MM were entered in the study with the median follow-up of 86.4 months. By immunohistochemistry (IHC), IKZF1 and IKZF3 were expressed in 72 and 58% of the cases, respectively. IKZF1 and IKZF3 expressions were associated with longer median progression free survival (P = 0.0029 and P < 0.0001) and overall survival (P = 0.0014 and P < 0.0001). IKZF3 expression also appears predicted a favorable response to the lenalidomide-based therapy.
Nelson J Chao - One of the best experts on this subject based on the ideXlab platform.
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pan pim kinase inhibitors enhance lenalidomide s anti myeloma activity via cereblon ikzf1 3 cascade
Cancer Letters, 2019Co-Authors: Jing Zheng, Yonggang Sha, Logan Roof, Oded Foreman, John Lazarchick, Jagadish Kummetha Venkta, Cleopatra Kozlowski, Cristina Gasparetto, Nelson J ChaoAbstract:Abstract Multiple myeloma remains an incurable disease, and continued efforts are required to develop novel agents and novel drug combinations with more effective anti-myeloma activity. Here, we show that the pan-PIM kinase inhibitors SGI1776 and CX6258 exhibit significant anti-myeloma activity and that combining a pan-PIM kinase inhibitor with the immunomodulatory agent lenalidomide in an in vivo myeloma xenograft mouse model resulted in synergistic myeloma cell killing without additional hematologic or hepatic toxicities. Further investigations indicated that treatment with a pan-PIM kinase inhibitor promoted increased ubiquitination and subsequent degradation of IKZF1 and IKZF3, two transcription factors crucial for survival of myeloma cells. Combining a pan-PIM kinase inhibitor with lenalidomide led to more effective degradation of IKZF1 and IKZF3 in multiple myeloma cell lines as well as xenografts of myeloma tumors. We also demonstrated that treatment with a pan-PIM kinase inhibitor resulted in increased expression of cereblon, and that knockdown of cereblon via a shRNA lentivirus abolished the effects of PIM kinase inhibition on the degradation of IKZF1 and IKZF3 and myeloma cell apoptosis, demonstrating a central role of cereblon in pan-PIM kinase inhibitor-mediated down-regulation of IKZF1 and IKZF3 and myeloma cell killing. These data elucidate the mechanism of pan-PIM kinase inhibitor mediated anti-myeloma effect and the rationale for the synergy observed with lenalidomide co-treatment, and provide justification for a clinical trial of the combination of pan-PIM kinase inhibitors and lenalidomide for the treatment of multiple myeloma.
