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Molecular Cancer May 2024Proteolysis-targeting chimeras (PROTACs) technology has garnered significant attention over the last 10 years, representing a burgeoning therapeutic approach with the... (Review)
Review
Proteolysis-targeting chimeras (PROTACs) technology has garnered significant attention over the last 10 years, representing a burgeoning therapeutic approach with the potential to address pathogenic proteins that have historically posed challenges for traditional small-molecule inhibitors. PROTACs exploit the endogenous E3 ubiquitin ligases to facilitate degradation of the proteins of interest (POIs) through the ubiquitin-proteasome system (UPS) in a cyclic catalytic manner. Despite recent endeavors to advance the utilization of PROTACs in clinical settings, the majority of PROTACs fail to progress beyond the preclinical phase of drug development. There are multiple factors impeding the market entry of PROTACs, with the insufficiently precise degradation of favorable POIs standing out as one of the most formidable obstacles. Recently, there has been exploration of new-generation advanced PROTACs, including small-molecule PROTAC prodrugs, biomacromolecule-PROTAC conjugates, and nano-PROTACs, to improve the in vivo efficacy of PROTACs. These improved PROTACs possess the capability to mitigate undesirable physicochemical characteristics inherent in traditional PROTACs, thereby enhancing their targetability and reducing off-target side effects. The new-generation of advanced PROTACs will mark a pivotal turning point in the realm of targeted protein degradation. In this comprehensive review, we have meticulously summarized the state-of-the-art advancements achieved by these cutting-edge PROTACs, elucidated their underlying design principles, deliberated upon the prevailing challenges encountered, and provided an insightful outlook on future prospects within this burgeoning field.
Topics: Humans; Proteolysis; Neoplasms; Antineoplastic Agents; Animals; Proteasome Endopeptidase Complex; Molecular Targeted Therapy; Ubiquitin-Protein Ligases; Proteolysis Targeting Chimera
PubMed: 38773495
DOI: 10.1186/s12943-024-02024-9 -
American Society of Clinical Oncology... Jun 2024Despite significant improvement in the outcomes of patients with newly diagnosed multiple myeloma (NDMM) with novel therapies, there is still an underserved high-risk... (Review)
Review
Despite significant improvement in the outcomes of patients with newly diagnosed multiple myeloma (NDMM) with novel therapies, there is still an underserved high-risk (HR) population that experiences early disease progression and death. With the median survival crossing 10 years, we defined ultrahigh-risk (uHR)MM as MM leading to death within 24-36 months of diagnosis and HRMM as MM leading to death within 36-60 months. Several features have emerged as markers of uHRMM: the co-occurrence of two or more high-risk cytogenetic abnormalities, extramedullary disease, plasma cell leukemia and a high-risk gene expression profiling signature. The heterogeneous risk definition across trials, the few trials available designed for HR patients, and the small HR subgroups in all-comers trials make it difficult to generate recommendations with high levels of evidence. Nevertheless, regardless of treatment administered, several studies consistently showed that achieving and maintaining measurable residual disease negativity is now considered the main factor able to mitigate the adverse prognosis related to baseline features. For fit patients with HR transplant-eligible (TE) NDMM, quadruplet induction/consolidation treatment with anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors and dexamethasone, and autologous stem-cell transplant and maintenance with, if available, at least a doublet combination could be considered the option of choice. For non-TE NDMM, considering the recent data generated and carefully reviewing those upcoming, quadruplet treatment consisting of anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors, and dexamethasone should also be considered. Future trials integrating BCMA-directed novel generation immunotherapies hold great potential for further advancing the treatment landscape in all NDMM patients with HR disease.
Topics: Humans; Multiple Myeloma; Prognosis; Risk Factors; Antineoplastic Combined Chemotherapy Protocols; Risk Assessment
PubMed: 38772002
DOI: 10.1200/EDBK_433520 -
Journal of Cancer Research and Clinical... May 2024Carfilzomib, commonly used for relapsed/refractory multiple myeloma (RRMM), has been associated with various adverse events in randomized controlled trials (RCTs).... (Observational Study)
Observational Study
PURPOSE
Carfilzomib, commonly used for relapsed/refractory multiple myeloma (RRMM), has been associated with various adverse events in randomized controlled trials (RCTs). However, real-world safety data for a more diverse population are needed, as carfilzomib received expedited approval. This study aimed to evaluate carfilzomib's safety in Korea by comparing new users of KRd (carfilzomib, lenalidomide, and dexamethasone) to Rd (lenalidomide and dexamethasone) using a nationwide administrative claims database.
METHODS
The retrospective cohort study utilized target trial emulation, focusing on adverse events in various organ systems similar to the ASPIRE trial.
RESULTS
This study included 4,580 RRMM patients between 2007 and 2020, and the KRd group showed significantly higher risks of hematologic adverse events (anemia, neutropenia, thrombocytopenia) and some non-hematologic adverse events (cough, hypokalemia, constipation, hypertension, heart failure) compared to the Rd group. Among non-hematologic adverse events, cardiovascular events (heart failure [HR 2.04; 95% CI 1.24-3.35], hypertension [HR 1.58; 95% CI 1.15-2.17]) had the highest risk in the KRd group.
CONCLUSION
The safety profile of carfilzomib in Korean patients was similar to previous RCTs. Therefore, caution should be exercised when using carfilzomib in Asian individuals with RRMM due to the increased risk of cardiovascular adverse events.
Topics: Humans; Multiple Myeloma; Oligopeptides; Male; Female; Republic of Korea; Retrospective Studies; Middle Aged; Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Neoplasm Recurrence, Local; Lenalidomide
PubMed: 38769166
DOI: 10.1007/s00432-024-05800-8 -
PLoS Biology May 2024Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In...
Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In order to expand the application of alkenyl oxindoles for targeted protein degradation, we designed and synthesized a series of heterobifunctional compounds by conjugating different alkenyl oxindoles with bromodomain-containing protein 4 (BRD4) inhibitor JQ1. Through structure-activity relationship study, we successfully developed JQ1-alkenyl oxindole conjugates that potently degrade BRD4. Unexpectedly, we found that these molecules degrade BRD4 through the ubiquitin-proteasome system, rather than the autophagy-lysosomal pathway. Using pooled CRISPR interference (CRISPRi) screening, we revealed that JQ1-alkenyl oxindole conjugates recruit the E3 ubiquitin ligase complex CRL4DCAF11 for substrate degradation. Furthermore, we validated the most potent heterobifunctional molecule HL435 as a promising drug-like lead compound to exert antitumor activity both in vitro and in a mouse xenograft tumor model. Our research provides new employable proteolysis targeting chimera (PROTAC) moieties for targeted protein degradation, providing new possibilities for drug discovery.
Topics: Humans; Animals; Proteolysis; Mice; Ubiquitin-Protein Ligases; Oxindoles; Cell Cycle Proteins; Transcription Factors; Cell Line, Tumor; Xenograft Model Antitumor Assays; Mice, Nude; HEK293 Cells; Structure-Activity Relationship; Proteasome Endopeptidase Complex; Azepines; Antineoplastic Agents; Female; Bromodomain Containing Proteins; Receptors, Interleukin-17
PubMed: 38768083
DOI: 10.1371/journal.pbio.3002550 -
Journal of the American Heart... May 2024Many cardiomyopathy-associated pathogenic variants are heterozygous truncations, and pathogenic variants are associated with arrhythmias. Arrhythmia triggers in...
BACKGROUND
Many cardiomyopathy-associated pathogenic variants are heterozygous truncations, and pathogenic variants are associated with arrhythmias. Arrhythmia triggers in filaminopathy are incompletely understood.
METHODS AND RESULTS
We describe an individual with biallelic pathogenic variants, p.Arg650X and c.970-4A>G, with peripartum cardiomyopathy and ventricular arrhythmias. We also describe clinical findings in probands with variants including Val2715fs87X, Glu2458Serfs71X, Phe106Leu, and c.970-4A>G with hypertrophic and dilated cardiomyopathy, atrial fibrillation, and ventricular tachycardia. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated. The truncation, Arg650X/c.970-4A>G, showed a marked reduction in filamin C protein consistent with biallelic loss of function mutations. To assess loss of filamin C, gene editing of a healthy control iPSC line was used to generate a homozygous disruption in the actin binding domain. Because filamin C has been linked to protein quality control, we assessed the necessity of filamin C in iPSC-CMs for response to the proteasome inhibitor bortezomib. After exposure to low-dose bortezomib, null iPSC-CMs showed an increase in the chaperone proteins BAG3, HSP70 (heat shock protein 70), and HSPB8 (small heat shock protein B8) and in the autophagy marker LC3I/II. null iPSC-CMs had prolonged electric field potential, which was further prolonged in the presence of low-dose bortezomib. null engineered heart tissues had impaired function after low-dose bortezomib.
CONCLUSIONS
pathogenic variants associate with a predisposition to arrhythmias, which can be modeled in iPSC-CMs. Reduction of filamin C prolonged field potential, a surrogate for action potential, and with bortezomib-induced proteasome inhibition, reduced filamin C led to greater arrhythmia potential and impaired function.
Topics: Filamins; Humans; Proteostasis; Female; Induced Pluripotent Stem Cells; Arrhythmias, Cardiac; Myocytes, Cardiac; Cardiomyopathies; Male; Adult; Mutation; Bortezomib
PubMed: 38761081
DOI: 10.1161/JAHA.123.030467 -
Cancer Research Communications Jun 2024Proteasomes degrade intracellular proteins to generate antigenic peptides that are recognized by the adaptive immune system and promote anticancer immunity. However,...
UNLABELLED
Proteasomes degrade intracellular proteins to generate antigenic peptides that are recognized by the adaptive immune system and promote anticancer immunity. However, tumors subvert the antigen presentation machinery to escape immunosurveillance. We hypothesized that proteasome activation could concomitantly increase antigen abundance and diversity in multiple myeloma cells. High-throughput screens revealed that histone deacetylase 6 (HDAC6) inhibitors activated proteasomes to unmask neoantigens and amplify the tumor-specific antigenic landscape. Treatment of patient CD138+ cells with HDAC6 inhibitors significantly promoted the antimyeloma activity of autologous CD8+ T cells. Pharmacologic blockade and genetic ablation of the HDAC6 ubiquitin-binding domain released HR23B, which shuttles ubiquitinylated cargo to proteasomes, while silencing HDAC6 or HR23B in multiple myeloma cells abolished the effect of HDAC6 inhibitors on proteasomes, antigen presentation, and T-cell cytotoxicity. Taken together, our results demonstrate the paradigm-shifting translational impact of proteasome activators to expand the myeloma immunopeptidome and have revealed novel, actionable antigenic targets for T cell-directed immunotherapy.
SIGNIFICANCE
The elimination of therapy-resistant tumor cells remains a major challenge in the treatment of multiple myeloma. Our study identifies and functionally validates agents that amplify MHC class I-presented antigens and pave the way for the development of proteasome activators as immune adjuvants to enhance immunotherapeutic responses in patients with multiple myeloma.
Topics: Humans; Histone Deacetylase 6; Proteasome Endopeptidase Complex; Multiple Myeloma; Histone Deacetylase Inhibitors; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Antigen Presentation; Antigens, Neoplasm
PubMed: 38747592
DOI: 10.1158/2767-9764.CRC-23-0528 -
BioRxiv : the Preprint Server For... May 2024The transcriptional coactivators EP300 and CREBBP are critical regulators of gene expression that share high sequence identity but exhibit non-redundant functions in...
The transcriptional coactivators EP300 and CREBBP are critical regulators of gene expression that share high sequence identity but exhibit non-redundant functions in basal and pathological contexts. Here, we report the development of a bifunctional small molecule, MC-1, capable of selectively degrading EP300 over CREBBP. Using a potent aminopyridine-based inhibitor of the EP300/CREBBP catalytic domain in combination with a VHL ligand, we demonstrate that MC-1 preferentially degrades EP300 in a proteasome-dependent manner. Mechanistic studies reveal that selective degradation cannot be predicted solely by target engagement or ternary complex formation, suggesting additional factors govern paralogue-specific degradation. MC-1 inhibits cell proliferation in a subset of cancer cell lines and provides a new tool to investigate the non-catalytic functions of EP300 and CREBBP. Our findings expand the repertoire of EP300/CREBBP-targeting chemical probes and offer insights into the determinants of selective degradation of highly homologous proteins.
PubMed: 38746397
DOI: 10.1101/2024.05.03.592353 -
BioRxiv : the Preprint Server For... May 2024Circadian clock genes are emerging targets in many types of cancer, but their mechanistic contributions to tumor progression are still largely unknown. This makes it...
Circadian clock genes are emerging targets in many types of cancer, but their mechanistic contributions to tumor progression are still largely unknown. This makes it challenging to stratify patient populations and develop corresponding treatments. In this work, we show that in breast cancer, the disrupted expression of circadian genes has the potential to serve as biomarkers. We also show that the master circadian transcription factors (TFs) BMAL1 and CLOCK are required for the proliferation of metastatic mesenchymal stem-like (mMSL) triple-negative breast cancer (TNBC) cells. Using currently available small molecule modulators, we found that a stabilizer of cryptochrome 2 (CRY2), the direct repressor of BMAL1 and CLOCK transcriptional activity, synergizes with inhibitors of proteasome, which is required for BMAL1 and CLOCK function, to repress a transcriptional program comprising circadian cycling genes in mMSL TNBC cells. Omics analyses on drug-treated cells implied that this repression of transcription is mediated by the transcription factor binding sites (TFBSs) features in the cis-regulatory elements (CRE) of clock-controlled genes. Through a massive parallel reporter assay, we defined a set of CRE features that are potentially repressed by the specific drug combination. The identification of -element enrichment may serve as a new way of defining and targeting tumor types through the modulation of -regulatory programs, and ultimately provide a new paradigm of therapy design for cancer types with unclear drivers like TNBC.
PubMed: 38746115
DOI: 10.1101/2024.04.26.590360 -
Journal of Experimental & Clinical... May 2024Mounting evidences shows that the ubiquitin‒proteasome pathway plays a pivotal role in tumor progression. The expression of 26S proteasome non-ATPase regulatory...
BACKGROUND
Mounting evidences shows that the ubiquitin‒proteasome pathway plays a pivotal role in tumor progression. The expression of 26S proteasome non-ATPase regulatory subunit 9 (PSMD9) is correlated with recurrence and radiotherapy resistance in several tumor types. However, the role and mechanism of PSMD9 in hepatocellular carcinoma (HCC) progression remain largely unclear.
METHODS
PSMD9 was identified as a prognosis-related biomarker for HCC based on analysis of clinical characteristics and RNA-seq data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and the JP Project of the International Cancer Genome Consortium (ICGC-LIRI-JP). PSMD9 expression was analyzed in cancer tissues and adjacent noncancerous tissues via immunohistochemistry and Western blotting. Multiple in vivo and in vitro experimental techniques (such as CCK-8, colony formation, EdU, and Transwell assays; flow cytometry; Western blotting; quantitative RT-PCR; Coimmunoprecipitation assay and immunofluorescence confocal imaging) were used to assess the functions of PSMD9 in the pathogenesis of HCC.
RESULTS
We found that the expression of PSMD9 was upregulated and associated with a poor prognosis in HCC patients. PSMD9 promoted HCC cell proliferation, migration, invasion and metastasis. Knockdown of PSMD9 significantly inhibited HCC cell proliferation by inducing G1/S cell cycle arrest and apoptosis. Mechanistically, we demonstrated that PSMD9 promoted HCC cell proliferation and metastasis via direct interaction with the E3 ubiquitin ligase c-Cbl, suppresses EGFR ubiquitination, influenced EGFR endosomal trafficking and degradation and subsequently activated ERK1/2 and Akt signaling. In addition, we showed that PSMD9 knockdown sensitized HCC cells to the tyrosine kinase inhibitor erlotinib in vitro and in vivo.
CONCLUSIONS
Collectively, our results indicate that PSMD9 drives HCC progression and erlotinib resistance by suppressing c-Cbl mediated EGFR ubiquitination and therefore can be a potential therapeutic target for HCC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Proto-Oncogene Proteins c-cbl; ErbB Receptors; Mice; Animals; Signal Transduction; Disease Progression; Male; Female; Cell Line, Tumor; Proteasome Endopeptidase Complex; Cell Proliferation; Prognosis; Mice, Nude; Apoptosis; Middle Aged; Cell Movement
PubMed: 38745188
DOI: 10.1186/s13046-024-03062-3 -
Nature Communications May 2024The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an...
The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an undifferentiated cancer with high mortality. We show here that depletion of the PIAS2 beta isoform with a transcribed double-stranded RNA-directed RNA interference (PIAS2b-dsRNAi) specifically inhibits growth of ATC cell lines and patient primary cultures in vitro and of orthotopic patient-derived xenografts (oPDX) in vivo. Critically, PIAS2b-dsRNAi does not affect growth of normal or non-anaplastic thyroid tumor cultures (differentiated carcinoma, benign lesions) or cell lines. PIAS2b-dsRNAi also has an anti-cancer effect on other anaplastic human cancers (pancreas, lung, and gastric). Mechanistically, PIAS2b is required for proper mitotic spindle and centrosome assembly, and it is a dosage-sensitive protein in ATC. PIAS2b depletion promotes mitotic catastrophe at prophase. High-throughput proteomics reveals the proteasome (PSMC5) and spindle cytoskeleton (TUBB3) to be direct targets of PIAS2b SUMOylation at mitotic initiation. These results identify PIAS2b-dsRNAi as a promising therapy for ATC and other aggressive anaplastic carcinomas.
Topics: Humans; Protein Inhibitors of Activated STAT; Animals; Cell Line, Tumor; Mitosis; Mice; Thyroid Neoplasms; RNA Interference; Spindle Apparatus; Molecular Chaperones; Xenograft Model Antitumor Assays; Proteasome Endopeptidase Complex; Sumoylation; Carcinoma; Female
PubMed: 38744818
DOI: 10.1038/s41467-024-47751-1