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Bioorganic & Medicinal Chemistry Nov 2023Proteolysis-targeting chimera (PROTAC) technology is a disruptive innovation in the drug development community, and over 20 PROTAC molecules are currently under clinical...
Proteolysis-targeting chimera (PROTAC) technology is a disruptive innovation in the drug development community, and over 20 PROTAC molecules are currently under clinical evaluation. These PROTAC molecules contain small-molecule warheads that bind to target proteins. Recently, oligonucleotide-warheaded PROTACs have emerged as a promising new tool to degrade DNA-binding proteins such as transcription factors. In this study, we applied an oligonucleotide-warheaded PROTAC technology to induce the degradation of signal transducer and activator of transcription 3 (STAT3), which is a hard-to-target protein. A double-stranded decoy oligonucleotide specific to STAT3 was conjugated to E3 binders (pomalidomide, VH032, and LCL161) to generate PROTAC molecules that recruited different E3 ubiquitin ligases cereblon (CRBN), von Hippel-Lindau (VHL), and inhibitor of apoptosis protein (IAP), respectively. One of the resulting PROTAC molecules, POM-STAT3, which recruits CRBN, potently induces STAT3 degradation. STAT3 degradation by POM-STAT3 was abolished by scrambling the oligonucleotide sequences of POM-STAT3 and by adding a double-stranded decoy oligonucleotide against STAT3 in a competitive manner, suggesting the significance of oligonucleotide sequences in STAT3 degradation. Moreover, POM-STAT3-induced STAT3 degradation was suppressed by the CRBN binder thalidomide, proteasome inhibitor bortezomib, E1 inhibitor MLN7243, and siRNA-mediated depletion of CRBN, indicating that STAT3 degradation is mediated by the ubiquitin-proteasome system, which involves CRBN as the responsible E3 ubiquitin ligase. Consistent with STAT3 degradation, NCI-H2087 cell viability was severely reduced following POM-STAT3 treatment. Thus, POM-STAT3 is a STAT3 degrader that potentially has cytocidal activity against cancer cells that are highly dependent on STAT3 signaling, which implies that inducing protein degradation by decoy oligonucleotide-warheaded PROTAC molecules could be harnessed to be therapeutic against oncogenic transcription factors.
Topics: STAT3 Transcription Factor; Ubiquitin-Protein Ligases; Proteolysis; Proteasome Endopeptidase Complex; Ubiquitins
PubMed: 37922656
DOI: 10.1016/j.bmc.2023.117507 -
Nature Communications Nov 2023Temporal control of protein levels in cells and living animals can be used to improve our understanding of protein function. In addition, control of engineered proteins...
Temporal control of protein levels in cells and living animals can be used to improve our understanding of protein function. In addition, control of engineered proteins could be used in therapeutic applications. PRoteolysis-TArgeting Chimeras (PROTACs) have emerged as a small-molecule-driven strategy to achieve rapid, post-translational regulation of protein abundance via recruitment of an E3 ligase to the target protein of interest. Here, we develop several PROTAC molecules by covalently linking the antibiotic trimethoprim (TMP) to pomalidomide, a ligand for the E3 ligase, Cereblon. These molecules induce degradation of proteins of interest (POIs) genetically fused to a small protein domain, E. coli dihydrofolate reductase (eDHFR), the molecular target of TMP. We show that various eDHFR-tagged proteins can be robustly degraded to 95% of maximum expression with PROTAC molecule 7c. Moreover, TMP-based PROTACs minimally affect the expression of immunomodulatory imide drug (IMiD)-sensitive neosubstrates using proteomic and biochemical assays. Finally, we show multiplexed regulation with another known degron-PROTAC pair, as well as reversible protein regulation in a rodent model of metastatic cancer, demonstrating the formidable strength of this system. Altogether, TMP PROTACs are a robust approach for selective and reversible degradation of eDHFR-tagged proteins in vitro and in vivo.
Topics: Animals; Tetrahydrofolate Dehydrogenase; Proteolysis Targeting Chimera; Escherichia coli Proteins; Escherichia coli; Trimethoprim; Proteomics; Ubiquitin-Protein Ligases; Proteolysis
PubMed: 37923771
DOI: 10.1038/s41467-023-42820-3 -
Blood Advances Dec 2023
Topics: Humans; Multiple Myeloma; Bortezomib; Thalidomide; Renal Insufficiency; Dexamethasone
PubMed: 37922425
DOI: 10.1182/bloodadvances.2023011428 -
Der Nervenarzt Feb 2024Primary central nervous system lymphomas (PCNSL) are rare highly aggressive diffuse large B cell non-Hodgkin lymphomas confined to the brain, meninges, the spinal cord... (Review)
Review
Primary central nervous system lymphomas (PCNSL) are rare highly aggressive diffuse large B cell non-Hodgkin lymphomas confined to the brain, meninges, the spinal cord and the eyes. Although the implementation of high-dose methotrexate-based chemotherapy has significantly improved the prognosis of PCNSL during the last decades, about one third of patients show refractory disease and about half of the patients eventually relapse after having achieved complete response. This highlights the need for novel treatment strategies. The most promising progress has been made in the field of molecular targeted therapy that interferes with the oncogenic signaling pathways of PCNSL. These include inhibitors of Bruton tyrosine kinase and inhibitors of the PI3K/mTOR signaling pathway. In addition, the thalidomide analogues lenalidomide and pomalidomide, which belong to the class of immunomodulators, show efficacy in the treatment of PCNSL. As immune evasion appears to play a relevant pathogenetic role in PCNSL, immunotherapies in the treatment of PCNSL are the subject of intensive research. Promising initial clinical data are available for both immune checkpoint inhibitors and cellular immunotherapy with chimeric antigen receptor (CAR) T cells. Before the widespread clinical application of these novel therapies, the efficacy needs to be confirmed in larger prospective studies. Despite high response rates, targeted therapies and immunotherapy often fail to achieve lasting tumor control. Therefore, novel approaches are currently being investigated in combination protocols.
Topics: Humans; Lymphoma, Non-Hodgkin; Prospective Studies; Neoplasm Recurrence, Local; Lymphoma; Central Nervous System; Central Nervous System Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37910181
DOI: 10.1007/s00115-023-01561-w -
Journal of Medicinal Chemistry Nov 2023Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common cereblon (CRBN) recruiters in proteolysis-targeting chimera...
Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common cereblon (CRBN) recruiters in proteolysis-targeting chimera (PROTAC) design. However, these CRBN ligands induce the degradation of IMiD neosubstrates and are inherently unstable, degrading hydrolytically under moderate conditions. In this work, we simultaneously optimized physiochemical properties, stability, on-target affinity, and off-target neosubstrate modulation features to develop novel nonphthalimide CRBN binders. These efforts led to the discovery of conformationally locked benzamide-type derivatives that replicate the interactions of the natural CRBN degron, exhibit enhanced chemical stability, and display a favorable selectivity profile in terms of neosubstrate recruitment. The utility of the most potent ligands was demonstrated by their transformation into potent degraders of BRD4 and HDAC6 that outperform previously described reference PROTACs. Together with their significantly decreased neomorphic ligase activity on IKZF1/3 and SALL4, these ligands provide opportunities for the design of highly selective and potent chemically inert proximity-inducing compounds.
Topics: Proteolysis; Proteolysis Targeting Chimera; Ubiquitin-Protein Ligases; Ligands; Nuclear Proteins; Transcription Factors; Adaptor Proteins, Signal Transducing
PubMed: 37902300
DOI: 10.1021/acs.jmedchem.3c00851 -
[Rinsho Ketsueki] the Japanese Journal... 2023Multiple myeloma (MM) is a hematological malignancy characterized by aberrant clonal plasma cells in the bone marrow. Despite significant advances in the treatment of...
Multiple myeloma (MM) is a hematological malignancy characterized by aberrant clonal plasma cells in the bone marrow. Despite significant advances in the treatment of MM, infection remains a main cause of death. MM patients have an increased risk of infection compared to their healthy counterparts due to several factors related to underlying disease, advanced age, comorbidities, and MM treatment. MM patients are at high risk of infection during the first 3 months after diagnosis and during relapse. Anti-myeloma drugs frequently result in severe immunosuppression and increased risk of infection. Proteasome inhibitors deplete T cells, lenalidomide and pomalidomide induce neutropenia, and CD38 antibodies reduce B cell function. To prevent infection in MM patients, we should take appropriate action by medical prophylaxis and vaccination.
Topics: Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Lenalidomide; Antibodies; Proteasome Inhibitors
PubMed: 37899186
DOI: 10.11406/rinketsu.64.1083 -
Journal of Oncology Pharmacy Practice :... Jan 2024Elotuzumab in combination with dexamethasone and immunomodulating agents (IMiDs) lenalidomide or pomalidomide is 2nd to 4th line therapy for multiple myeloma. The...
Elotuzumab in combination with dexamethasone and immunomodulating agents (IMiDs) lenalidomide or pomalidomide is 2nd to 4th line therapy for multiple myeloma. The labelled dosage of dexamethasone for use in conjunction with elotuzumab and IMiDs splits the dexamethasone dose into two administrations, one oral and one intravenous, on the days of each elotuzumab infusion. Administration of split dose dexamethasone on days of elotuzumab administration is based on the registration trials submitted for drug approval and was intended to ensure standard well-timed immunotherapy premedication using pharmacologically equivalent dexamethasone doses for both study arms. Administration of dexamethasone in the manner delineated by the elotuzumab product label adds complexity to the delivery of care. This commentary provides an empirical assessment of established medication safety and effectiveness which supports administration of dexamethasone standard intermittent dose instead of the split dose approach delineated on elotuzumab package insert. Simplification of regimen administration improves medication adherence, reduces the risk of inadvertent omission or duplication of medication therapy, and improves the workflow required for delivery of care.
Topics: Humans; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols; Multiple Myeloma; Immunomodulating Agents; Antibodies, Monoclonal, Humanized
PubMed: 37876226
DOI: 10.1177/10781552231207855 -
Zhongguo Shi Yan Xue Ye Xue Za ZhiTo investigate the efficacy and safety of pomalidomide based regimen in the treatment of high-risk multiple myeloma (MM).
OBJECTIVE
To investigate the efficacy and safety of pomalidomide based regimen in the treatment of high-risk multiple myeloma (MM).
METHODS
Clinical data of 27 high-risk MM patients treated in Shanxi Bethune Hospital from January 2021 to December 2022 were retrospectively analyzed. All patients were treated with pomadomide based regimen for at least 2 consecutive cycles, and the early therapeutic effect and safety were observed.
RESULTS
Overall remission rate (ORR) was 63.0%(17/27 cases) and deep remission rate was 22.2%(6/27 cases) after 2 cycles of treatment; ORR was 90.5%(19/21 cases) and deep remission rate was 66.7%(14/21 cases) after 4 cycles of treatment. Both ORR and deep remission rate were significantly higher after 4 cycles of treatment than 2 cycles (=0.044, =0.003). Beyond that, in the newly diagnosed and relapsed refractory MM groups, ORR after 2 cycles of treatment were 75%(9/12 cases) and 60%(9/15 cases), and deep remission rates were 25%(3/12 cases) and 20%(3/15 cases), respectively; ORR after 4 cycles of treatment were 100%(9/9 cases) and 83.3%(10/12 cases), and deep remission rates were 77.8%(7/9 cases) and 58.3%(7/12 cases), respectively, while there was no significant difference in remission rates between the two groups (>0.05). In the group of creatinine ≥177 μmol/L, the serum creatinine level was significantly decreased after 2 cycles of treatment compared with that pre-treatment (=0.001). The 1q21 amplified subgroup accounted for the largest proportion (21/27 cases), ORR was 66.7%(14/21 cases) and deep remission rate was 23.8%(5/21 cases) after 2 cycles of treatment, ORR was 88.9%(16/18 cases) and deep remission rate was 66.7%(12/18 cases) after 4 cycles of treatment. In all the symptoms, the most common adverse reactions were pulmonary infection in 9 cases and hematological adverse reactions of grade 1-2 in 8 cases.
CONCLUSION
The pomalidomide-based treatment regimen has good early curative effect on the newly diagnosed and relapsed refractory high-risk MM, and also benefits to the high-risk cytogenetic MM, or MM with renal impairment. Therefore, this treatment regimen showed a good safety, and the long-term curative effect needs to be further assessed by more clinical data.
PubMed: 37846696
DOI: 10.19746/j.cnki.issn.1009-2137.2023.05.028 -
Cancers Oct 2023Daratumumab-based combinations with pomalidomide/dexamethasone (DPd), or bortezomib/dexamethasone (DVd), have shown activity in relapsed/refractory multiple myeloma...
Efficacy and Safety of Daratumumab, Pomalidomide, and Dexamethasone (DPd) Compared to Daratumumab, Bortezomib, and Dexamethasone (DVd) in Daratumumab-Naïve Relapsed Multiple Myeloma.
Daratumumab-based combinations with pomalidomide/dexamethasone (DPd), or bortezomib/dexamethasone (DVd), have shown activity in relapsed/refractory multiple myeloma (RRMM) patients. However, no direct comparisons of safety or efficacy of the two regimens have been published to date. We conducted a retrospective study to compare the safety and efficacy of DPd and DVd in daratumumab-naïve RRMM patients. We included 140 daratumumab-naïve patients who had received DPd or DVd for RRMM. Overall, the DPd group had a greater number of patients who had high-risk disease characteristics. Although response was deeper in the DPd group, the median progression-free survival (PFS) and overall survival (OS) were similar between the two groups. The DPd group exhibited a higher incidence of hematologic toxicities, whereas the DVd group had a higher incidence of peripheral neuropathy. The study results showed that while DPd may provide a deeper response, there was no significant difference in PFS or OS compared to DVd. For the high proportion of difficult-to-treat patients, duration of treatment may have contributed to these results, indicating that patient and disease characteristics should be considered when selecting salvage treatments.
PubMed: 37835587
DOI: 10.3390/cancers15194894