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Science (New York, N.Y.) Jun 2023Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease and human African trypanosomiasis (HAT)....
Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease and human African trypanosomiasis (HAT). Improved HAT treatments are available, but Chagas disease therapies rely on two nitroheterocycles, which suffer from lengthy drug regimens and safety concerns that cause frequent treatment discontinuation. We performed phenotypic screening against trypanosomes and identified a class of cyanotriazoles (CTs) with potent trypanocidal activity both in vitro and in mouse models of Chagas disease and HAT. Cryo-electron microscopy approaches confirmed that CT compounds acted through selective, irreversible inhibition of trypanosomal topoisomerase II by stabilizing double-stranded DNA:enzyme cleavage complexes. These findings suggest a potential approach toward successful therapeutics for the treatment of Chagas disease.
Topics: Animals; Humans; Mice; Chagas Disease; Cryoelectron Microscopy; DNA Topoisomerases, Type II; Trypanosoma; Topoisomerase II Inhibitors; Triazoles; Trypanosomiasis, African; Drug Evaluation, Preclinical
PubMed: 37384702
DOI: 10.1126/science.adh0614 -
Journal of Clinical Oncology : Official... Dec 2023Patritumab deruxtecan, or HER3-DXd, is an antibody-drug conjugate consisting of a fully human monoclonal antibody to human epidermal growth factor receptor 3 (HER3)...
HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy.
PURPOSE
Patritumab deruxtecan, or HER3-DXd, is an antibody-drug conjugate consisting of a fully human monoclonal antibody to human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. We assessed the efficacy and safety of HER3-DXd in patients with epidermal growth factor receptor ()-mutated non-small-cell lung cancer (NSCLC).
METHODS
This phase II study (ClinicalTrials.gov identifier: NCT04619004) was designed to evaluate HER3-DXd in patients with advanced mutated NSCLC previously treated with EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy (PBC). Patients received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks or an uptitration regimen (3.2 → 4.8 → 6.4 mg/kg). The primary end point was confirmed objective response rate (ORR; RECIST 1.1) by blinded independent central review (BICR), with a null hypothesis of 26.4% on the basis of historical data.
RESULTS
Enrollment into the uptitration arm closed early on the basis of a prespecified benefit-risk assessment of data from the phase I U31402-A-U102 trial. In total, 225 patients received HER3-DXd 5.6 mg/kg once every 3 weeks. As of May 18, 2023, median study duration was 18.9 (range, 14.9-27.5) months. Confirmed ORR by BICR was 29.8% (95% CI, 23.9 to 36.2); median duration of response, 6.4 months; median progression-free survival, 5.5 months; and median overall survival, 11.9 months. The subgroup of patients with previous osimertinib and PBC had similar outcomes. Efficacy was observed across a broad range of pretreatment tumor HER3 membrane expression levels and across diverse mechanisms of EGFR TKI resistance. In patients with nonirradiated brain metastases at baseline (n = 30), the confirmed CNS ORR by BICR per CNS RECIST was 33.3% (95% CI, 17.3 to 52.8). The safety profile (National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) was manageable and tolerable, consistent with previous observations.
CONCLUSION
After tumor progression with EGFR TKI therapy and PBC in patients with -mutated NSCLC, HER3-DXd once every 3 weeks demonstrated clinically meaningful efficacy with durable responses, including in CNS metastases. A phase III trial in mutated NSCLC after progression on an EGFR TKI is ongoing (HERTHENA-Lung02; ClinicalTrials.gov identifier: NCT05338970).
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Platinum; ErbB Receptors; Mutation; Protein Kinase Inhibitors
PubMed: 37689979
DOI: 10.1200/JCO.23.01476 -
Bioorganic Chemistry Jul 2023The DNA topoisomerase enzymes are widely distributed throughout all spheres of life and are necessary for cell function. Numerous antibacterial and cancer... (Review)
Review
The DNA topoisomerase enzymes are widely distributed throughout all spheres of life and are necessary for cell function. Numerous antibacterial and cancer chemotherapeutic drugs target the various topoisomerase enzymes because of their roles in maintaining DNA topology during DNA replication and transcription. Agents derived from natural products, like anthracyclines, epipodophyllotoxins and quinolones, have been widely used to treat a variety of cancers. A very active field of fundamental and clinical research is the selective targeting of topoisomerase II enzymes for cancer treatment. This thematic review summarizes the recent advances in the anticancer activity of the most potent topoisomerase II inhibitors (anthracyclines, epipodophyllotoxins and fluoroquinolones) their modes of action, and structure-activity relationships (SARs) organized chronologically in the last ten years from 2013 to 2023. The review also highlights the mechanism of action and SARs of promising new topoisomerase II inhibitors.
Topics: Topoisomerase II Inhibitors; Antineoplastic Agents; Antibiotics, Antineoplastic; DNA Topoisomerases, Type II; Podophyllotoxin; Anthracyclines; Topoisomerase I Inhibitors
PubMed: 37094479
DOI: 10.1016/j.bioorg.2023.106548 -
Nature Communications Oct 2023Type IIA topoisomerases are essential DNA processing enzymes that must robustly and reliably relax DNA torsional stress. While cellular processes constantly create...
Type IIA topoisomerases are essential DNA processing enzymes that must robustly and reliably relax DNA torsional stress. While cellular processes constantly create varying torsional stress, how this variation impacts type IIA topoisomerase function remains obscure. Using multiple single-molecule approaches, we examined the torsional dependence of eukaryotic topoisomerase II (topo II) activity on naked DNA and chromatin. We observed that topo II is ~50-fold more processive on buckled DNA than previously estimated. We further discovered that topo II relaxes supercoiled DNA prior to plectoneme formation, but with processivity reduced by ~100-fold. This relaxation decreases with diminishing torsion, consistent with topo II capturing transient DNA loops. Topo II retains high processivity on buckled chromatin (~10,000 turns) and becomes highly processive even on chromatin under low torsional stress (~1000 turns), consistent with chromatin's predisposition to readily form DNA crossings. This work establishes that chromatin is a major stimulant of topo II function.
Topics: DNA Topoisomerases, Type II; DNA; Chromatin; DNA Topoisomerases, Type I; Eukaryotic Cells
PubMed: 37891161
DOI: 10.1038/s41467-023-42600-z -
Cytokine Aug 2023For more than 40 years, the epipodophyllotoxin drug etoposide is prescribed to treat cancer. This semi-synthetic compound remains extensively used to treat advanced... (Review)
Review
For more than 40 years, the epipodophyllotoxin drug etoposide is prescribed to treat cancer. This semi-synthetic compound remains extensively used to treat advanced small-cell lung cancer and in various chemotherapy regimen for autologous stem cell transplantation, and other anticancer protocols. Etoposide is a potent topoisomerase II poison, causing double-stranded DNA breaks which lead to cell death if they are not repaired. It is also a genotoxic compound, responsible for severe side effects and secondary leukemia occasionally. Beyond its well-recognized function as an inducer of cancer cell death (a "killer on the road"), etoposide is also useful to treat immune-mediated inflammatory diseases associated with a cytokine storm syndrome. The drug is essential to the treatment of hemophagocytic lymphohistiocytosis (HLH) and the macrophage activation syndrome (MAS), in combination with a corticosteroid and other drugs. The use of etoposide to treat HLH, either familial or secondary to a viral or parasitic infection, or treatment-induced HLH and MAS is reviewed here. Etoposide dampens inflammation in HLH patients via an inhibition of the production of pro-inflammatory mediators, such as IL-6, IL-10, IL-18, IFN-γ and TNF-α, and reduction of the secretion of the alarmin HMGB1. The modulation of cytokines production by etoposide contributes to deactivate T cells and to dampen the immune stimulation associated to the cytokine storm. This review discussed the clinical benefits and mechanism of action of etoposide (a "rider on the storm") in the context of immune-mediated inflammatory diseases, notably life-threatening HLH and MAS. The question arises as to whether the two faces of etoposide action can apply to other topoisomerase II inhibitors.
Topics: Humans; Etoposide; Cytokine Release Syndrome; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Lymphohistiocytosis, Hemophagocytic; Macrophage Activation Syndrome
PubMed: 37269699
DOI: 10.1016/j.cyto.2023.156234 -
Cell Death and Differentiation Mar 2024Cisplatin-based chemotherapy improves the control of distant metastases in patients with nasopharyngeal carcinoma (NPC); however, around 30% of patients fail treatment...
Cisplatin-based chemotherapy improves the control of distant metastases in patients with nasopharyngeal carcinoma (NPC); however, around 30% of patients fail treatment due to acquired drug resistance. Epigenetic regulation is known to contribute to cisplatin resistance; nevertheless, the underlying mechanisms remain poorly understood. Here, we showed that lysine-specific demethylase 5B (KDM5B) was overexpressed and correlates with tumor progression and cisplatin resistance in patients with NPC. We also showed that specific inhibition of KDM5B impaired the progression of NPC and reverses cisplatin resistance, both in vitro and in vivo. Moreover, we found that KDM5B inhibited the expression of ZBTB16 by directly reducing H3K4me3 at the ZBTB16 promoter, which subsequently increased the expression of Topoisomerase II- α (TOP2A) to confer cisplatin resistance in NPC. In addition, we showed that the deubiquitinase USP7 was critical for deubiquitinating and stabilizing KDM5B. More importantly, the deletion of USP7 increased sensitivity to cisplatin by disrupting the stability of KDM5B in NPC cells. Therefore, our findings demonstrated that USP7 stabilized KDM5B and promoted cisplatin resistance through the ZBTB16/TOP2A axis, suggesting that targeting KDM5B may be a promising cisplatin-sensitization strategy in the treatment of NPC.
Topics: Humans; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Epigenesis, Genetic; Jumonji Domain-Containing Histone Demethylases; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Nuclear Proteins; Promyelocytic Leukemia Zinc Finger Protein; Repressor Proteins; Ubiquitin-Specific Peptidase 7
PubMed: 38287116
DOI: 10.1038/s41418-024-01257-x -
Antibiotics (Basel, Switzerland) Jul 2023The extensive use of fluoroquinolones has been consequently accompanied by the emergence of bacterial resistance, which triggers the necessity to discover new compounds.... (Review)
Review
The extensive use of fluoroquinolones has been consequently accompanied by the emergence of bacterial resistance, which triggers the necessity to discover new compounds. Delafloxacin is a brand-new anionic non-zwitterionic fluoroquinolone with some structural particularities that give it attractive proprieties: high activity under acidic conditions, greater in vitro activity against Gram-positive bacteria-even those showing resistance to currently-used fluoroquinolones-and nearly equivalent affinity for both type-II topoisomerases (i.e., DNA gyrase and topoisomerase IV). During phases II and III clinical trials, delafloxacin showed non-inferiority compared to standard-of-care therapy in the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia, which resulted in its approval in 2017 by the Food and Drug Administration for indications. Thanks to its overall good tolerance, its broad-spectrum in vitro activity, and its ease of use, it could represent a promising molecule for the treatment of bacterial infections.
PubMed: 37627661
DOI: 10.3390/antibiotics12081241