FNDR-11124, a broad-spectrum small molecule inhibitor of viral RNA polymerase, restricts replication of SARS-CoV-2 and Influenza virus in vitro and in vivo.

The poly (ADP-ribose) polymerase (PARP) inhibitor talazoparib, in combination with the androgen receptor pathway inhibitor enzalutamide, has demonstrated improved survival outcomes compared with enzalutamide monotherapy in homologous recombination repair mutations (HRRm)-positive metastatic castration-resistant prostate cancers (mCRPC) in the TALAPRO-2 trial. However, potential cost-effectiveness of the combination regimen remains limited. Our objective was to evaluate lifetime cost-effectiveness of talazoparib plus enzalutamide (TALA + ENZA) versus enzalutamide (ENZA) alone from a U.S. payer perspective. A partitioned survival model with progression-free survival (PFS) and overall survival (OS) inputs were derived from the TALAPRO-2. Costs for drugs, adverse events, disease management, and end-of-life care were included. Health outcomes included life-years (LYs) and quality-adjusted life-years (QALYs). Incremental cost-effectiveness ratios (ICERs) were calculated for TALA + ENZA versus ENZA. Deterministic and probabilistic sensitivity analyses assessed parameter uncertainty, and scenario analyses explored drug price reductions and shorter time horizons. In the base case, TALA + ENZA yielded 4.84 total LYs and 3.25 QALYs, compared with 3.27 LYs and 1.95 QALYs for ENZA alone, resulting in incremental gains of 1.57 LYs and 1.30 QALYs. Total costs were $1,544,791 for TALA+ENZA and $378,932 for ENZA, yielding an ICER of $896,159 per QALY gained. Sensitivity analyses identified utility and drug cost inputs as the most influential parameters. Probabilistic analysis showed a 50% probability of cost-effectiveness at a willingness-to-pay (WTP) threshold of approximately $1.0 million/QALY gained. For HRRm-positive mCRPC, TALA+ENZA provided survival and QALY gains compared with ENZA alone but at higher cost, resulting in an ICER exceeding typical U.S. WTP thresholds.

• Organoboron compounds have attracted increased attention in the field of medicinal chemistry due to their ability to elicit direct drug-enzyme interactions. Our intent was to explore boron containing heterocycles as poly(ADP-ribose) polymerase (PARP) inhibitors. • In this study, we have created a series of boron-containing heterocyclic compounds that includes 21 benzoxazaborinin derivatives, in yields ranging from 20% to 99%. • We were able to synthesize benzoxazaborinin-based PARP inhibitors, with molecule 15A displaying the best potency with the lowest IC50 value of 31 mM. • Overall, we have shown that benzoxazaborinins can serve as effective PARP inhibitors in the mM range. The inhibition of poly(ADP-Ribose) polymerase (PARP) has been utilized therapeutically for the treatment of BRCA-deficient breast, ovarian and prostate cancer. Organoboron compounds have attracted increased attention in the field of medicinal chemistry due to their ability to elicit direct drug-enzyme interactions. In this study, we have created a series of boron-containing heterocyclic compounds that includes 21 benzoxazaborinin derivatives, in yields ranging from 20% to 99%. These benzoxazaborinin compounds are characterized by utilizing NMR spectroscopy and HRMS, and tested for PARP inhibition with a PARP-1 screening assay, which is both cost-effective and does not require special laboratory equipment. Overall, we were able to synthesize benzoxazaborinin-based PARP inhibitors, which are utilized as breast and ovarian cancer drugs. Molecule 15A displays the best potency with the lowest IC50 value of 31 μM.

Immunotherapy in triple-negative breast cancer: From molecular mechanisms to precision medicine-overcoming resistance and optimizing clinical outcomes.

In prostate cancer (PCa), smoking history is associated with more aggressive clinicopathological features, reduced efficacy of androgen deprivation therapy, and poorer overall survival (OS). However, its impact on survival outcomes in patients receiving taxane chemotherapy, poly ADP-ribose polymerase inhibitor (PARPi), or immune checkpoint inhibitor (ICI) therapy for PCa remains unclear. We compared the genetic profiles of smokers and non-smokers with PCa in several public databases to explore the potential influence of smoking on treatment outcomes. We retrospectively collected data on smoking history, tumor characteristics, genomic information, treatment history, and survival outcomes from three public databases to investigate the role of smoking in PCa. Patients were categorized into smokers and non-smokers, and associations between smoking history and clinicopathological features, genetic profiles, and treatment outcomes were analyzed. Independent risk factors for OS were evaluated using multivariate Cox proportional hazard regression models. Smokers exhibited significantly higher Gleason score, clinical stage, tumor mutational burden, fraction genome altered, and microsatellite instability scores than non-smokers. The survival analysis revealed that smokers had significantly poorer OS than non-smokers in the overall, hormone therapy, and PARPi therapy cohorts. In contrast, no significant difference in OS was observed between the taxane chemotherapy and ICI therapy cohorts. Furthermore, multivariate Cox proportional hazard regression analysis identified smoking history as an independent risk factor for OS in the overall, hormone therapy, and PARPi therapy cohorts. Oncoplot analysis showed a significantly higher frequency of TP53 mutations and PTEN copy number alterations in smokers than in non-smokers. Smoking history was significantly associated with aggressive clinicopathological features and a poor prognosis in patients with PCa. Our findings suggest that smokers with PCa may receive greater benefit from the early administration of taxane chemotherapy in comparison to other treatment regimens.

Feline infectious peritonitis virus (FIPV) poses a significant threat to cats worldwide. Besides the limited development of antiviral drugs that mainly target virus proteins, concerns about resistance to mutant strains - similar to those seen in human and other mammalian viruses - remain high. Therefore, addressing these challenges involves developing innovative antiviral therapies, such as host-directed treatments that target host cell processes essential for viral replication. FIPV infection induced distinctive dynamics of lipid droplet (LD) remodelling, characterized by an increase in LD abundance from early to mid-infection, followed by a subsequent decline. Phosphorylated hormone-sensitive lipase, a key mediator of LD hydrolysis and fatty-acid release, became activated after the mid-infection phase, potentially contributing to elevated intracellular fatty-acid availability during late infection. Notably, atglistatin (DABPU-DM) and its derivatives robustly suppressed FIPV replication in Crandell-Rees feline kidney (CRFK) and feline macrophage Fcwf-4 cells, coincident with preservation of LD integrity and inhibition of LD breakdown. Among these compounds, DABPU-DE had the best selectivity index (686.0±35.2) against FIPV, with a higher half-maximal cytotoxic concentration (274.4±3.6 µM) and a lower half-maximal inhibitory concentration (0.4±0.02 µM). Moreover, combining DABPU-DE (0.18 µM) with remdesivir (1.35 µM), a viral RNA-dependent RNA polymerase inhibitor, showed a very strong synergistic effect (CI=0.09 and Bliss synergy score=14.46±1.80) in inhibiting FIPV replication in CRFK cells, even at lower doses than either drug alone. In conclusion, DABPU-DE is a promising antiviral candidate for FIPV, and its synergistic effect with remdesivir warrants further research in cats infected with FIPV.

Background: Brush biopsy is a minimally invasive method for early detection of oral squamous cell carcinoma (OSCC). Enhanced accuracy for clinical utility depends on analysis of the whole cell population and automated cohort classifications. Aim: This study aims to delineate OSCC, high-grade dysplasia (HGD), and low-risk lesions (LRLs) by profiling single-cell level alterations using multiplexed flow cytometry. Methods: Brush-biopsy samples were analyzed from patients with LRL, HGD, and OSCC. Flow cytometry analysis was standardized to ascertain cell distribution, heterogeneity, and epithelial cell content. Markers were used for epithelial cell (Pan-Cytokeratin [Pan-CK]/ propidium iodide [PI]) and atypical cell (Sambucus–Nigra–Agglutinin-1 [SNA-1]/ polyadenosine diphosphate-ribose polymerase inhibitor [PARPi-FL]) delineation. In addition, scatter properties and molecular-equivalence fluorescence (MEF) values of markers were analyzed for cohort classification. Results: Brush-biopsy samples from OSCC/HGD patients showed heterogeneity in the percentage of Pan-CK+ve/PI+ve cells. Significant variation in MEF values of SNA-1/PARPi-FL/PI delineated the OSCC cohort (area under the curve > 0.85). Furthermore, the markers in combination with scatter properties delineated OSCC (multivariate logistic regression; sensitivity: 90%, specificity: 82%). The analysis of the forward-scatter height-to-area ratio delineated HGD from low-risk lesions by capturing the morphology-based cellular differences. Conclusions: These results suggest that a flow cytometry-based analysis of brushbiopsy samples may serve as an adjunct tool for risk stratification of oral lesions. Relevance for patients: This study provides evidence towards the application of flow cytometry as an objective, quantitative adjunct to conventional cytology, and improves early detection and risk stratification of oral lesions using a minimally invasive sampling method, thereby supporting timely clinical decision-making and patient management.

DNA damage and repair mechanisms are crucial for maintaining genomic stability, and their dysregulation is closely linked to the complex pathogenesis of autoimmune diseases. The present review systematically describes the types of DNA damage, key repair pathways, their regulatory networks, and the multidimensional interactions between DNA repair and the immune system. Furthermore, it delves into how defective DNA repair drives the development of autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis through mechanisms encompassing cyclic GMP‑AMP synthase (cGAS)‑stimulator of interferon genes (STING) pathway activation, self‑antigen release and breakdown of immune tolerance. Oxidative stress‑induced DNA damage, mutations in repair genes and aberrant accumulation of cytosolic DNA are key triggers of autoimmune responses. In addition, DNA repair proteins indirectly influence disease progression by modulating immune cell functions, including T‑cell homeostasis and macrophage polarization. The present review further summarizes the therapeutic potential and challenges of targeting DNA damage response pathways, including via poly adenosine diphosphate ribose polymerase inhibitors and cGAS‑STING axis regulation, as demonstrated in pre‑clinical models. Future research leveraging multi‑omics and innovative delivery systems will be crucial for translating these discoveries into effective, personalized therapies. The present review advances the development of personalized precision medicine and provides a solid theoretical foundation for developing novel treatment strategies.

Objective: This article presents a summary of the 2025 Swedish prostate cancer guidelines, focusing on recurrence after local treatment, metastatic disease, and castration-resistant prostate cancer. Results: The 2025 Swedish guidelines introduce several important updates. Prostate specific membrane antigen (PSMA)-PET/CT is recommended only when PSA exceeds 0.2 µg/L, and reporting should follow the defined PSMA-RADS-scale. PSMA-PET/CT is preferred over lymph-node dissection for staging. A strong recommendation is issued for radiotherapy to the primary tumour in all oligometastatic men with a life expectancy > 5 years, whereas metastasis-directed therapy is restricted to clinical trials. Systemic treatment pathways now prioritise androgen receptor pathway inhibitors (ARPI) plus androgen deprivation therapy (ADT), with triple therapy (including docetaxel) used more selectively. Pathway-specific staging algorithms have been revised. The oly (ADP-ribose) polymerase inhibitor (PARPi) section has expanded, with broader genomic-based selection and integration into treatment sequencing. Two new chapters and an appendix address cardiovascular risk assessment before ARPI or chemotherapy. Supportive care is substantially strengthened.Compared with the EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer 2025, the Swedish guidelines 2025 applies PSMA-PET/CT more conservatively, restricts PSMA-guided nodal salvage therapy, and issues a more universal recommendation for local radiotherapy in oligometastatic disease. The Swedish guidelines 2025 prioritise ARPI + ADT and limit triple therapy and PARPi combinations due to regulatory and reimbursement constraints. PARPi are largely reserved for BRCA1/2-mutated disease. The Swedish guidelines 2025 provide a more comprehensive framework for rehabilitation and survivorship. Conclusions: The 2025 Swedish prostate cancer guidelines introduce multiple new recommendations and differ in several aspects from the European guidelines.

Overall survival with relacorilant and nab-paclitaxel in patients with platinum-resistant ovarian cancer (ROSELLA): a phase 3 randomised controlled trial.

There are four FDA-approved poly (ADP-ribose) polymerase inhibitors (PARPi) for treating metastatic castration-resistant prostate cancer. However, dose-limiting toxicities may reduce efficacy when treatment is de-escalated. Identifying modulators of PARPi sensitivity could enable combination strategies that enhance efficacy while minimizing toxicity. This study investigates whether Protein kinase D1 (PrKD1), recently discovered to modulate DNA repair, influences sensitivity to PARP inhibition. We used prostate cancer cell lines with altered PrKD1 expression to assess viability following olaparib and/or Compound-10, a selective PrKD1 inhibitor, treatment. Subcellular fractionation, immunoprecipitation, in silico modeling and Western blotting of lysates of cells and tumor samples harvested from patient-derived xenograft tumor engrafted mice treated with Compound-10 were used to evaluate protein expression, interaction, and localization. PrKD1-overexpressing C4-2 cells exhibited significantly increased sensitivity to growth inhibition by olaparib. Downregulation of PrKD1 in LNCaP cells conferred resistance. Biochemical inhibition of PrKD1 by Compound-10 also enhanced sensitivity. Co-immunoprecipitation experiments demonstrated that PrKD1 and PARP1 are present in the same immunocomplex, and PrKD1 transfection in C4-2 cells increased PARP1 membrane localization. Treatment of prostate cancer PDX models with Compound-10 increased PARP1 expression. In silico molecular modeling identified a site adjacent to the PARP1 WGR domain potentially binding to multiple PrKD1 domains. Our study identifies PrKD1 as a novel modulator of sensitivity to olaparib. Co-targeting PrKD1 using small molecular inhibitors may enhance olaparib efficacy at lower doses and improve PARPi tolerability and therapeutic index. The demonstration of PARP1 at the membrane is novel, introducing the possibility of targeting membranous PARP1 for theranostic applications.

Background: Niraparib is selective poly (ADP-ribose) polymerase (PARP) inhibitor employed preliminary to mitigate ovarian, fallopian tube, or peritoneal cancer. Accurate and reliable analytical strategy is pivotal in quality control of niraparib in pharmaceuticals. Objective of current investigation is to develop as well as validate straightforward, rapid, precise, robust Reversed-phase high-performance liquid chromatography (RP-HPLC) strategy for quantitative determination of niraparib, with stability-indicating capability, in compliance with International Council for Harmonisation (ICH) guidelines. Method: Chromatographic separation was accomplished employing Agilent Zorbax Bonus-RP column (4.6 mm × 250 mm, 5 µm particle size). Mobile phase consisted of 0.1% trifluoroacetic acid (TFA) in water and acetonitrile in a 75:25 v/v ratio, delivered in isocratic mode at flow rate of 1.0 mL/min. Detection wavelength was set at 240 nm, as well as injection volume was optimized at 20 µL. Method was validated for specificity, linearity, accuracy, precision, limit of detection (LOD), limit of quantification (LOQ), along with robustness. Result: Niraparib eluted with good peak symmetry and resolution with retention duration of 5.18 minutes. With R2 > 0.999, method revealed linearity in concentration range of 40–60 µg/mL. Results explored that LOD was 1.42 µg/mL and LOQ was 4.30 µg/mL. With Relative standard deviation (RSD) of less than 2%, intra- and interday precision results were within appropriate limits, demonstrating great precision. Additionally, approach exhibited outstanding accuracy and robustness under varied conditions. Conclusion: Developed RP-HPLC strategy was straightforward, accurate, precise, sensitive, as well as reliable. It is apt for regular stability testing and quality control analysis of niraparib in pharmaceuticals and bulk drugs. Its potential to suggest stability guarantees that it may be availed to monitor drug stability under variety of stress conditions and identify degradation products.

Treatment options for metastatic prostate cancer have evolved and diversified considerably in recent years. In the hormone-sensitive setting (mHSPC), the combination of androgen deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPI) or abiraterone + prednis(ol)one (Abi), optionally combined with docetaxel, represents the current standard of care. Prior therapy, the principle of switching the mechanism of action, and the patient's individual molecular genetic profile substantially influence treatment selection in the metastatic castration-resistant setting (mCRPC). Testing for genes involved in homologous recombination repair (HRR), particularly BRCA1/2, is essential for the indication of poly(ADP-ribose) polymerase inhibitors (PARPI), which can be used as monotherapy or in combination with an ARPI/Abi, and has prognostic as well as familial implications. Radioligand therapy with lutetium (177Lu) vipivotide tetraxetan has also gained increasing importance. It is indicated for mCRPC after prior treatment with ARPI/Abi and taxane chemotherapy, and may already play arole in the first-line mCRPC setting following treatment with darolutamide + ADT + docetaxel in mHSPC. This article presents current guideline recommendations for mHSPC and mCRPC, summarizes the underlying evidence, and provides practical guidance for treatment selection based on prior therapy and individual genetic profiles in order to support optimal decision-making in an increasingly complex therapeutic landscape.

Olaparib, a poly ADP-ribose polymerase inhibitor, was approved by the European Commission in December 2022 and for which the Health for technology Assessment (HtA body) issued a favorable opinion for reimbursement in France on 5 April, 2023, following the results of the PROpel phase III clinical trial, for the first-line treatment of metastatic castration-resistant prostate cancer in combination with abiraterone and prednisone or prednisolone in adult men for whom chemotherapy is not clinically indicated. This publication aimed to report the first real-world data of patients with metastatic castration-resistant prostate cancer who received a combination of first-line olaparib with abiraterone, plus prednisone or prednisolone in the funded Early Access (fEA) for olaparib in France, from 30 March, 2023, to 25 September, 2024. Eligible patients were adult men with first-line metastatic castration-resistant prostate cancer. Olaparib 300-mg twice-daily tablets was given in combination with abiraterone plus prednisone or prednisolone regardless of the homologous recombination repair gene mutation status. Characteristics of the population, treatment duration, reasons for discontinuation, and safety data were collected during the fEA period. Patients could continue to receive olaparib after the end of the fEA. A total of 84 physicians spread over 72 hospitals in metropolitan France requested a fEA for 176 patients, 154 (87.5%) of whom were eligible to be included in the early access program. In total, 118 (76.6%) patients had an unknown homologous recombination repair status. Half of the patients (76, 49.7%) had very aggressive cancer with a Gleason score of 8 while 11 (7.2%) of them had a low-grade cancer with a Gleason score of 6 at the diagnosis. The most common metastatic sites were bone (107 patients, 69.5%) and distant (60, 39.0%) or regional (42, 27.3%) lymph nodes. Among the 154 patients, 84 (54.5%) had medical history, 47 (56.0%) of whom had arterial hypertension. All included patients had received at least one prior treatment prior to the metastatic castration resistance stage. Most patients (145, 94.2%) had received androgen suppression and 70 (45.5%) had been treated with androgen receptor pathway inhibitors. Of the 154 patients, 153 (99.4%) had at least one concomitant treatment with abiraterone and prednisone or prednisolone. Data confirming administration of olaparib treatment were provided for 149 patients (exposed patients), of whom 140 (94.0%) received olaparib at initiation at the dose of 300 mg twice daily. Fifty-seven patients experienced a total of 60 adverse events (36 serious adverse events and 24 non-serious adverse events). Over this period, three fatal and five life-threatening events were reported. The three fatal adverse events were one death assessed as a suspected adverse reaction (pancytopenia) and two deaths assessed as unrelated to olaparib: one attributed to disease progression and one to suicide. Because of adverse events, dose reductions were made in five patients, treatment was temporarily interrupted in one patient and discontinued in 20 patients. These are the first results describing the real-world use of olaparib in France in prostate cancer. Most patients included in the fEA had generally similar characteristics as the patients randomized in the PROpel clinical trial (NCT03732820) and initiated at the standard dose of 300 mg twice daily. No new safety signals were reported in this real-world patient population. The analyzed data did not modify the benefit-risk balance of olaparib.

Germline BRCA1 and BRCA2 mutations enable targeted therapies in human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). The two poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors olaparib and talazoparib were introduced into clinical practice in 2018. Limited evidence about their routine clinical use highlights the importance of this analysis. We provide a real-world analysis for PARP-inhibitor use in ABC patients treated within the prospective German PRAEGNANT registry (NCT02338167). 152 patients with ABC receiving a PARP-inhibitor were included. Real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) were calculated for all patients using the Kaplan-Meier method. Subgroups (line of therapy, metastasis timing, hormone receptor (HR) status, treatment: olaparib, talazoparib, among others), germline BRCA1, BRCA2 and PALB2 mutations and adverse events (AEs) were analyzed. The median rwPFS was 6.2 months (95% CI, 4.8-7.9) and the median rwOS was 17.1 months (95% CI, 14.4-22.3). Line of therapy, HR status and treatment (olaparib versus talazoparib) appeared to especially affect both rwPFS and rwOS. Among patients with a reported germline mutation, 36.1% had a BRCA1, 62.9% a BRCA2 and 1.0% a PALB2 mutation. In summary, outcomes were comparable to those reported in pivotal trials despite later-line use of PARP-inhibitors in this analysis.

Intrinsic and acquired resistance to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) remains a major barrier in treating homologous recombination (HR) repair-deficient tumors, including those with germline or somatic BRCA1/2 mutations. Although PARPi are FDA approved for adjuvant treatment of locally advanced or metastatic breast cancer in patients with germline BRCA1/2 mutations, emerging data support their use as monotherapy in the neoadjuvant setting. Promising safety profiles of newer-generation PARPi further support this potential. However, resistance mechanisms specific to the neoadjuvant setting are poorly understood. To address this gap, we leveraged resources from a phase II neoadjuvant clinical trial (NCT03499353), analyzing tumors from patients with germline BRCA1/2 mutant breast tumors before and after six months of talazoparib monotherapy. Whole-transcriptome analyses were performed on these samples. Additionally, we established orthotopic patient-derived xenograft models from a subset of the patient tumors and conducted whole-exome and whole-transcriptome analysis. This integrative approach revealed both known and previously unknown PARPi resistance mechanisms. In one case, overexpression of BRN2, encoding a transcription factor that plays a critical role in neurogenesis, led to activation of ATR/RAD51 and STAT3 pathways, restoring HR repair. BRN2-driven resistance could be reversed with ATR and STAT3 inhibitors, resensitizing cells to talazoparib. In another, an HR repair proficient tumor subclone lacking Shieldin 2 expression expanded during treatment and accounted for intrinsic resistance. Our findings highlight the need to determine intrinsic and anticipate acquired resistance pathways in treatment-naïve tumors and support combining PARPi with targeted agents to improve outcomes in the neoadjuvant setting.

Breast cancer remains the leading cause of cancer-related mortality among women worldwide. Poly(ADP-ribose) polymerase (PARP) inhibitors have emerged as a critical therapeutic option, particularly for patients with triple-negative breast cancer and other HER2-negative metastatic breast cancer harboring BRCA mutations. Despite their clinical success, the emergence of primary and acquired resistance to PARP inhibitors poses a significant challenge, limiting their long-term effectiveness. Here we provide a comprehensive overview of the mechanisms underlying the action of PARP inhibitors, as well as their clinical development and application. In addition, we discuss the factors driving resistance and potential strategies to overcome it in the context of PARP inhibitors.

The nucleotide-addition cycle (NAC) of multi-subunit DNA-dependent RNA polymerases (RNAPs) involves coordinated conformational changes in conserved active-site structural elements, including the trigger loop (TL). The TL is open (unfolded) in most RNAP structures but can close (fold) in substrate-bound (post- or pre-translocated) states of the RNAP, promoting catalysis. TL closure has been associated with closure of another conserved structural element, the Rim-Helices/F-loop (RH-FL), but the role of the RH-FL in the NAC is unclear. Antibiotic leads CBR9379 and AAP-SO 2 inhibit the Escherichia coli and Mycobacterium tuberculosis RNAPs, respectively, by binding in a pocket formed by the bridge helix and RH-FL. The precise mechanism of action for these inhibitors is yet to be defined. We present cryo-electron microscopy structures showing that both compounds inhibit the RNAP NAC by preventing RH-FL closure, thereby allosterically destabilizing the closed TL. This work reveals a conserved mechanistic principle of RNAP catalysis across all domains of life and provides new insight for antibiotic design.

Nonsegmented negative-sense RNA viruses (nsNSVs) rely on a multifunctional RNA-dependent RNA polymerase (RdRP) complex for transcription and replication. In measles virus (MeV), the nonstructural protein C has long been implicated in regulating RNA synthesis, yet its precise role remains unclear. Here, we show that the MeV C protein directly associates with the RdRP complex. Using cryoelectron microscopy, we determined atomic-resolution structures of the MeV polymerase with and without C, revealing that C binding stabilizes the C-terminal region of L and locks the complex into a replication-competent elongation state. Biochemical data further show that C promotes N protein recruitment, enhancing polymerase processivity through facilitating encapsidation during replication. Additionally, we also resolved high-resolution structures of MeV and Nipah virus (NiV) polymerases bound to ERDRP-0519, an orally available morbillivirus inhibitor. Unexpectedly, the compound occupies an allosteric pocket within the RdRp domain rather than the previously predicted PRNTase domain, overlapping conserved resistance sites. This binding induces conformational changes in palm subdomain, blocking RNA template and nucleotide engagement, thereby halting RNA synthesis. These findings uncover distinct regulatory and inhibitory mechanisms in paramyxovirus polymerases and provide a structural framework for the rational design of broad-spectrum antivirals targeting MeV, NiV, and potentially other clinically relevant nsNSVs.

Ovarian clear cell carcinomas (OCCC), particularly cases that retain wild-type AT-rich interactive domain 1 A (ARID1A) expression (approximately 50% of the OCCC cases), are chemoresistant and lack specific therapies. We identified BMAL2 as a critical OCCC oncogene that promotes tumorigenesis by preventing endogenous DNA damage. BMAL2 depletion altered the expression of genes encoding DNA damage repair proteins, including RAD51, a core enzyme of the homologous recombination (HR) pathway. This led to DNA double-stranded break accumulation, decreased cell viability and reduced tumor growth. This dependence on BMAL2 to maintain DNA integrity and cell viability can be a new route to suppress OCCC. Consistent with this idea, we found that GW833972A, a cannabinoid receptor agonist, bound BMAL2 with high affinity and facilitated its protein degradation. This in turn reduced RAD51 expression, leading to an accumulation of DNA damage, decreased cell viability and reduced OCCC tumor growth. GW833972A is effective by itself at high dose and can also be used at lower dosages to enhance the effectiveness of Poly (ADP-ribose) polymerase inhibitor (PARPi) treatments in BMAL2-expressing OCCC. Together, our findings reveal an essential oncogenic role of BMAL2 and demonstrate that it is an appealing therapeutic target, especially for ARID1A-wt OCCC.