Structural basis for the severe adverse interaction of sofosbuvir and amiodarone on L-type Cav channels.

Drug-drug interaction of the antiviral sofosbuvir and the antiarrhythmics amiodarone has been reported to cause fatal heartbeat slowing. Sofosbuvir and its analog, MNI-1, were reported to potentiate the inhibition of cardiomyocyte calcium handling by amiodarone, which functions as a multi-channel antagonist, and implicate its inhibitory effect on L-type Cav channels, but the molecular mechanism has remained unclear. Here we present systematic cryo-EM structural analysis of Cav1.1 and Cav1.3 treated with amiodarone or sofosbuvir alone, or sofosbuvir/MNI-1 combined with amiodarone. Whereas amiodarone alone occupies the dihydropyridine binding site, sofosbuvir is not found in the channel when applied on its own. In the presence of amiodarone, sofosbuvir/MNI-1 is anchored in the central cavity of the pore domain through specific interaction with amiodarone and directly obstructs the ion permeation path. Our study reveals the molecular basis for the physical, pharmacodynamic interaction of two drugs on the scaffold of Cav channels.

Pan-Cancer Proteomics Analysis to Identify Tumor-Enriched and Highly Expressed Cell Surface Antigens as Potential Targets for Cancer Therapeutics.

The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) provides unique opportunities for cancer target discovery using protein expression. Proteomics data from CPTAC tumor types have been primarily generated using a multiplex tandem mass tag (TMT) approach, which is designed to provide protein quantification relative to reference samples. However, relative protein expression data are suboptimal for prioritization of targets within a tissue type, which requires additional reprocessing of the original proteomics data to derive absolute quantitation estimation. We evaluated the feasibility of using differential protein analysis coupled with intensity-based absolute quantification (iBAQ) to identify tumor-enriched and highly expressed cell surface antigens, employing tandem mass tag (TMT) proteomics data from CPTAC. Absolute quantification derived from TMT proteomics data was highly correlated with that of label-free proteomics data from the CPTAC colon adenocarcinoma cohort, which contains proteomics data measured by both approaches. We validated the TMT-iBAQ approach by comparing the iBAQ value to the receptor density value of HER2 and TROP2 measured by flow cytometry in about 30 selected breast and lung cancer cell lines from the Cancer Cell Line Encyclopedia. Collections of these tumor-enriched and highly expressed cell surface antigens could serve as a valuable resource for the development of cancer therapeutics, including antibody-drug conjugates and immunotherapeutic agents.

Structure-Activity Relationship and Voltage Dependence for the Drug-Drug Interaction between Amiodarone Analogs and MNI-1 at the L-type Cav Channel.

The drug-drug interaction (DDI) between amiodarone (AMIO) and sofosbuvir (SOF), a direct-acting hepatitis-C NS5B nucleotide polymerase inhibitor, has been associated with severe bradyarrhythmia in patients. Recent cryo-EM data has revealed that this DDI occurs at the α-subunit of L-type Cav channels, with AMIO binding at the fenestration site and SOF [or MSD nucleotide inhibitor #1 (MNI-1): analog of SOF] binding at the central cavity of the conductance pathway. In this study, we investigated the DDI between 21 AMIO analogs, including dronedarone (DRON) and MNI-1 (or SOF) in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hCav1.2 models. Our findings indicate that among the tested AMIO analogs in hiPSC-CMs at clinically relevant concentrations, only three analogs (AA-9, AA-10, and AA-17) were able to effectively substitute for AMIO in this DDI with 1 µM MNI-1. This highlights the importance of the diethyl amino group of AMIO for interacting with MNI-1. In the hCav1.2 model, desethylamiodarone (AA-12) demonstrated synergy with 90 µM MNI-1, while three other analogs with modifications to the position of the diethyl amino group or removal of iodo groups showed weaker synergy with 90 µM MNI-1. Interestingly, DRON did not exhibit any interaction with 270 µM SOF or 90 µM MNI-1, suggesting that it could safely replace AMIO in patients requiring SOF treatment, other clinically relevant differences considered. Overall, our functional data align with the cryo-EM data, highlighting that this DDI is dependent on the structure of AMIO and cardiomyocyte resting membrane potential. SIGNIFICANCE STATEMENT: Our findings point to specific residues in the AMIO molecule playing a critical role in the DDI between AMIO and MNI-1 (SOF analog), confirming cryo-EM results. Applied at clinically relevant AMIO's concentrations or projected MNI-1's concentrations at the resting potentials mimicking the sinoatrial node, this DDI significantly slowed down or completely inhibited the beating of hiPSC-CMs. Finally, these in vitro results support the safe replacement of AMIO (Cordarone) with DRON (Multaq) for patients requiring SOF treatment, other clinical caveats considered.

Bridging molecular photosensitizer and catalyst on carbon nanotubes toward enhanced selectivity and durability for CO2 photoreduction.

Homogenous molecular photocatalysts for CO2 reduction, especially metal complex-based photosensitizer‒catalyst assemblages, have been attracting extensive research interests due to their efficiency and customizability. However, their low durability and recyclability limit practical applications. In this work, we immobilized the catalysts of metal terpyridyl complexes and the photosensitizer of [Ru(bpy)3]Cl2 onto the surface of carbon nanotubes through covalent bonds and electrostatic interactions, respectively, transforming the homogeneous system into a heterogeneous one. Our characterizations prove that these metal complexes are well dispersed on CNTs with a high loading (ca. 12 wt.%). Photocatalytic measurements reveal that catalytic activity is remarkably enhanced when the molecular catalysts are anchored, which is three times higher than that of homogeneous molecular catalysts. Moreover, when the photosensitizer of [Ru(bpy)3]Cl2 is immobilized, the side reaction of hydrogen evolution is completely suppressed and the selectivity for CO production reaches 100%, with its durability also significantly improved. This work provides an effective pathway for constructing heterogeneous photocatalysts based on rational assembly of efficient molecular photosensitizers and catalysts.

Salt-Stabilized Silylzinc Pivalates for Nickel-Catalyzed Carbosilylation of Alkenes.

We herein report the preparation of solid and salt-stabilized silylzinc pivalates from the corresponding silyllithium reagents via transmetalation with Zn(OPiv)2 . These resulting organosilylzinc pivalates show enhanced air and moisture stability and unique reactivity in the silylative difunctionalization of alkenes. Thus, a practical chelation-assisted nickel-catalyzed regioselective alkyl and benzylsilylation of alkenes has been developed, which provides an easy method to access alkyl silanes with broad substrate scope and wide functional group compatibility. Kinetic experiments highlight that the OPiv-coordination is crucial to improve the reactivity of silylzinc pivalates. Furthermore, late-stage functionalizations of druglike molecules and versatile modifications of the products illustrate the synthetical utility of this protocol.

Commensal microbiota contributes to predicting the response to immune checkpoint inhibitors in non-small-cell lung cancer patients.

Immunotherapy against cancer, through immune checkpoint inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 axis, is particularly successful in tumors by relieving the immune escape. However, interindividual responses to immunotherapy are often heterogeneous. Therefore, it is essential to screen out predictive tumor biomarkers. In this study, we analyzed the commensal microbiota in stool samples and paired sputum samples from 75 metastatic non-small-cell lung cancer (NSCLC) patients at baseline and during treatment with immune checkpoint inhibitors. Results showed distinct microbes' signatures between the gut microbiota and paired respiratory microbiota. The alpha diversity between the gut and respiratory microbiota was uncorrelated, and only the gut microbiota alpha diversity was associated with anti-programmed cell death-1 response. Higher gut microbiota alpha diversity indicated better response and more prolonged progression-free survival. Comparison of bacterial communities between responders and nonresponders showed some favorable/unfavorable microbes enriched in responders/nonresponders, indicating that commensal microbiota had potential predictive value for the response to immune checkpoint inhibitors. Generally, some rare low abundance gut microbes and high abundance respiratory microbes lead to discrepancies in microbial composition between responders and nonresponders. A significant positive correlation was observed between the abundance of Streptococcus and CD8+ T cells. These results highlighted the intimate relationship between commensal microbiota and the response to immunotherapy in NSCLC patients. Gut microbiota and respiratory microbiota are promising biomarkers to screen suitable candidates who are likely to benefit from immune checkpoint inhibitor-based immunotherapy.

Meningioma-associated protein 30 accelerates the proliferation and invasion of hepatocellular carcinoma by modulating Wnt/GSK-3ß/ß-catenin signaling.

Meningioma-associated protein 30 (MAC30) has been recently identified as a new tumor-associated protein that is implicated in multiple tumor types. However, the role of MAC30 in hepatocellular carcinoma (HCC) has not been studied. In the current study, we explored the expression, biological function and underlying mechanism of MAC30 in HCC. We found that MAC30 expression was significantly elevated in HCC tissues and cell lines. Functional in vitro assays demonstrated that the knockdown of MAC30 inhibited the proliferation and invasion of HCC cells, while MAC30 overexpression facilitated these biological behaviors. Moreover, the knockdown of MAC30 decreased glycogen synthase kinase (GSK)-3ß phosphorylation level and ß-catenin expression, leading to the inactivation of Wnt/ß-catenin signaling in HCC cells. The inhibition of GSK-3ß or reactivation Wnt/ß-catenin signaling markedly reversed MAC30 knockdown-mediated inhibitory effects on the proliferation and invasion of HCC cells. Notably, the inhibition of Wnt/ß-catenin signaling abrogated the MAC30-evoked oncogenic role in HCC cells. In addition, the knockdown of MAC30 impeded tumor formation and the growth rate of HCC cells in vivo. Taken together, our data recognized MAC30 as a potential tumor-promotion factor in HCC, which accelerated the proliferation and invasion of HCC through the up-regulation of Wnt/ß-catenin signaling. Our study suggests MAC30 as a potential anticancer target for HCC.

Regioselective Synthesis of 2,4-Diaryl-6-trifluoromethylated Pyridines through Copper-Catalyzed Cyclization of CF3-Ynones and Vinyl Azides.

A novel copper-catalyzed cyclization of readily available vinyl azides with CF3-ynones is steadily achieved under mild conditions to furnish the versatile 2,4-diaryl-6-trifluoromethylated pyridine products, which are of great interest in medicinal chemistry. The generation of the vinyl iminophosphorane intermediates from vinyl azides through the Staudinger-Meyer reaction ensures the subsequent 1,4-addition process with CF3-ynones in this transformation.

Identification of second-generation P2X3 antagonists for treatment of pain.

A second-generation small molecule P2X3 receptor antagonist has been developed. The lead optimization strategy to address shortcomings of the first-generation preclinical lead compound is described herein. These studies were directed towards the identification and amelioration of preclinical hepatobiliary findings, reducing potential for drug-drug interactions, and decreasing the projected human dose of the first-generation lead.

Clinical Features and Prognostic Factors in Elderly Ewing Sarcoma Patients.

BACKGROUND Elderly patients with Ewing sarcoma have a very poor prognosis, and treatment remains a challenge. However, the outcomes and potential prognostic factors of elderly Ewing sarcoma patients are rarely documented. Therefore, we investigated the prognosis of this special cohort and determine independent prognostic factors. MATERIAL AND METHODS A cohort of Ewing sarcoma patients aged over 40 years from 1973 to 2015 was identified from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. The Kaplan-Meier method and a Cox proportional hazard regression model were used for the prognostic analysis. RESULTS A total of 162 patients were included with a mean age of 53 years. The 5-year overall survival (OS) and cancer-specific survival (CSS) rates of the entire group were 43.7% and 47.9%, respectively. The sex, location, tumor size, and radiation treatment had no effect on survival outcomes on univariate analysis. Tumor stage, surgery, and chemotherapy were significant indicators of both OS and CSS on multivariable analysis. CONCLUSIONS Surgery in combination with chemotherapy had a significant survival benefit in elderly Ewing sarcoma patients and should be recommended.

Benzoxazolinone aryl sulfonamides as potent, selective Nav1.7 inhibitors with in vivo efficacy in a preclinical pain model.

Studies on human genetics have suggested that inhibitors of the Nav1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Nav1.7 inhibitors with excellent selectivity against the Nav1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Nav1.5 exceeding 1000-fold. Key structure-activity relationships associated with oral bioavailability were leveraged to discover compound 17, which exhibited a comparable potency/selectivity profile as well as full efficacy following oral administration in a preclinical model indicative of antinociceptive behavior.

Discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity and pharmacokinetics.

Selective inhibition of Kv1.5, which underlies the ultra-rapid delayed rectifier current, IKur, has been pursued as a treatment for atrial fibrillation. Here we describe the discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity versus the off-target current IKs, whose inhibition has been associated with ventricular proarrhythmia. MK-1832 exhibits improved selectivity for IKur over IKs (>3000-fold versus 70-fold for MK-0448), consistent with an observed larger window between atrial and ventricular effects in vivo (>1800-fold versus 210-fold for MK-0448). MK-1832 also exhibits an improved preclinical pharmacokinetic profile consistent with projected once daily dosing in humans.

Discovery of selective, orally bioavailable, N-linked arylsulfonamide Nav1.7 inhibitors with pain efficacy in mice.

The voltage-gated sodium channel Nav1.7 is a genetically validated target for the treatment of pain with gain-of-function mutations in man eliciting a variety of painful disorders and loss-of-function mutations affording insensitivity to pain. Unfortunately, drugs thought to garner efficacy via Nav1 inhibition have undesirable side effect profiles due to their lack of selectivity over channel isoforms. Herein we report the discovery of a novel series of orally bioavailable arylsulfonamide Nav1.7 inhibitors with high levels of selectivity over Nav1.5, the Nav isoform responsible for cardiovascular side effects, through judicious use of parallel medicinal chemistry and physicochemical property optimization. This effort produced inhibitors such as compound 5 with excellent potency, selectivity, behavioral efficacy in a rodent pain model, and efficacy in a mouse itch model suggestive of target modulation.

Interaction between amiodarone and hepatitis-C virus nucleotide inhibitors in human induced pluripotent stem cell-derived cardiomyocytes and HEK-293 Cav1.2 over-expressing cells.

Several clinical cases of severe bradyarrhythmias have been reported upon co-administration of the Hepatitis-C NS5B Nucleotide Polymerase Inhibitor (HCV-NI) direct-acting antiviral agent, sofosbuvir (SOF), and the Class-III anti-arrhythmic amiodarone (AMIO). We model the cardiac drug-drug interaction (DDI) between AMIO and SOF, and between AMIO and a closely-related SOF analog, MNI-1 (Merck Nucleotide Inhibitor #1), in functional assays of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), to provide mechanistic insights into recently reported clinical cases. AMIO co-applied with SOF or MNI-1 increased beating rate or field potential (FP) rate and decreased impedance (IMP) and Ca(2+) transient amplitudes in hiPSC-CM syncytia. This action resembled that of Ca(2+) channel blockers (CCBs) in the model, but CCBs did not substitute for AMIO in the DDI. AMIO analog dronedarone (DRON) did not substitute for, but competed with AMIO in the DDI. Ryanodine and thapsigargin, decreasing intracellular Ca(2+) stores, and SEA-0400, a Na(+)/Ca(2+) exchanger-1 (NCX1) inhibitor, partially antagonized or suppressed DDI effects. Other agents affecting FP rate only exerted additive or subtractive effects, commensurate with their individual effects. We also describe an interaction between AMIO and MNI-1 on Cav1.2 ion channels in an over-expressing HEK-293 cell line. MNI-1 enhanced Cav1.2 channel inhibition by AMIO, but did not affect inhibition of Cav1.2 by DRON, verapamil, nifedipine, or diltiazem. Our data in hiPSC-CMs indicate that HCV-NI agents such as SOF and MNI-1 interact with key intracellular Ca(2+)-handling mechanisms. Additional study in a Cav1.2 HEK-293 cell-line suggests that HCV-NIs potentiate the inhibitory action of AMIO on L-type Ca(2+) channels.

Glioblastoma: imaging genomic mapping reveals sex-specific oncogenic associations of cell death.

PURPOSE: To identify the molecular profiles of cell death as defined by necrosis volumes at magnetic resonance (MR) imaging and uncover sex-specific molecular signatures potentially driving oncogenesis and cell death in glioblastoma (GBM). MATERIALS AND METHODS: This retrospective study was HIPAA compliant and had institutional review board approval, with waiver of the need to obtain informed consent. The molecular profiles for 99 patients (30 female patients, 69 male patients) were identified from the Cancer Genome Atlas, and quantitative MR imaging data were obtained from the Cancer Imaging Archive. Volumes of necrosis at MR imaging were extracted. Differential gene expression profiles were obtained in those patients (including male and female patients separately) with high versus low MR imaging volumes of tumor necrosis. Ingenuity Pathway Analysis was used for messenger RNA-microRNA interaction analysis. A histopathologic data set (n = 368; 144 female patients, 224 male patients) was used to validate the MR imaging findings by assessing the amount of cell death. A connectivity map was used to identify therapeutic agents potentially targeting sex-specific cell death in GBM. RESULTS: Female patients showed significantly lower volumes of necrosis at MR imaging than male patients (6821 vs 11 050 mm(3), P = .03). Female patients, unlike male patients, with high volumes of necrosis at imaging had significantly shorter survival (6.5 vs 14.5 months, P = .01). Transcription factor analysis suggested that cell death in female patients with GBM is associated with MYC, while that in male patients is associated with TP53 activity. Additionally, a group of therapeutic agents that can potentially be tested to target cell death in a sex-specific manner was identified. CONCLUSION: The results of this study suggest that cell death in GBM may be driven by sex-specific molecular pathways.

Investigation of the effectiveness of a classification method based on improved DAE feature extraction for hepatitis C prediction.

Hepatitis C, a particularly dangerous form of viral hepatitis caused by hepatitis C virus (HCV) infection, is a major socio-economic and public health problem. Due to the rapid development of deep learning, it has become a common practice to apply deep learning to the healthcare industry to improve the effectiveness and accuracy of disease identification. In order to improve the effectiveness and accuracy of hepatitis C detection, this study proposes an improved denoising autoencoder (IDAE) and applies it to hepatitis C disease detection. Conventional denoising autoencoder introduces random noise at the input layer of the encoder. However, due to the presence of these features, encoders that directly add random noise may mask certain intrinsic properties of the data, making it challenging to learn deeper features. In this study, the problem of data information loss in traditional denoising autoencoding is addressed by incorporating the concept of residual neural networks into an enhanced denoising autoencoder. In our experimental study, we applied this enhanced denoising autoencoder to the open-source Hepatitis C dataset and the results showed significant results in feature extraction. While existing baseline machine learning methods have less than 90% accuracy and integrated algorithms and traditional autoencoders have only 95% correctness, the improved IDAE achieves 99% accuracy in the downstream hepatitis C classification task, which is a 9% improvement over a single algorithm, and a nearly 4% improvement over integrated algorithms and other autoencoders. The above results demonstrate that IDAE can effectively capture key disease features and improve the accuracy of disease prediction in hepatitis C data. This indicates that IDAE has the potential to be widely used in the detection and management of hepatitis C and similar diseases, especially in the development of early warning systems, progression prediction and personalised treatment strategies.

Neural network aided flexible joint optimization with design of experiment method for nuclear power plant inspection robot.

Introduction: The flexible joint is a crucial component for the inspection robot to flexible interaction with nuclear power facilities. This paper proposed a neural network aided flexible joint structure optimization method with the Design of Experiment (DOE) method for the nuclear power plant inspection robot. Methods: With this method, the joint's dual-spiral flexible coupler was optimized regarding the minimum mean square error of the stiffness. The optimal flexible coupler was demonstrated and tested. The neural network method can be used for the modeling of the parameterized flexible coupler with regard to the geometrical parameters as well as the load on the base of the DOE result. Results: With the aid of the neural network model of the stiffness, the dual-spiral flexible coupler structure can be fully optimized to a target stiffness, 450 Nm/rad in this case, and a given error level, 0.3% in the current case, with regard to the different loads. The optimal coupler is fabricated with wire electrical discharge machining (EDM) and tested. Discussion: The experimental results demonstrate that the load and angular displacement keep a good linear relationship in the given load range and this optimization method can be used as an effective method and tool in the joint design process.

Salt-stabilized alkylzinc pivalates: versatile reagents for cobalt-catalyzed selective 1,2-dialkylation.

The construction of Csp3-Csp3 bonds through Negishi-type reactions using alkylzinc reagents as the pronucleophiles is of great importance for the synthesis of pharmaceuticals and agrochemicals. However, the use of air and moisture sensitive solutions of conventional alkylzinc halides, which show unsatisfying reactivity and limitation of generality in twofold Csp3-Csp3 cross-couplings, still represents drawbacks. We herein report the first preparation of solid and salt-stabilized alkylzinc pivalates by OPiv-coordination, which exhibit enhanced stability and a distinct advantage of reacting well in cobalt-catalyzed difluoroalkylation-alkylation of dienoates, thus achieving the modular and site-selective installation of CF2- and Csp3-groups across double bonds in a stereoretentive manifold. This reaction proceeds under simple and mild conditions and features broad substrate scope and functional group compatibility. Kinetic experiments highlight that OPiv-tuning on the alkylzinc pivalates is the key for improving their reactivity in twofold Csp3-Csp3 cross-couplings. Furthermore, facile modifications of bioactive molecules and fluorinated products demonstrate the synthetical utility of our salt-stabilized alkylzinc reagents and cobalt-catalyzed alkyldifluoroalkylation protocol.

Stereoselective C-O silylation and stannylation of alkenyl acetates.

Facile formation of carbon-heteroatom bonds is a long-standing objective in synthetic organic chemistry. However, direct cross-coupling with readily accessible alkenyl acetates via inert C‒O bond-cleavage for the carbon-heteroatom bond construction remains challenging. Here we report a practical preparation of stereoselective tri- and tetrasubstituted alkenyl silanes and stannanes by performing cobalt-catalyzed C‒O silylation and stannylation of alkenyl acetates using silylzinc pivalate and stannylzinc chloride as the nucleophiles. This protocol features a complete control of chemoselectivity, stereoselectivity, as well as excellent functional group compatibility. The resulting alkenyl silanes and stannanes show high reactivities in arylation and alkenylation by Hiyama and Stille reactions. The synthetic utility is further illustrated by the facile late-stage modifications of natural products and drug-like molecules. Mechanistic studies suggest that the reaction might involve a chelation-assisted oxidative insertion of cobalt species to C‒O bond. We anticipate that our findings should prove instrumental for potential applications of this technology to organic syntheses and drug discoveries in medicinal chemistry.

Design and Preclinical Evaluation of a Novel B7-H4-Directed Antibody-Drug Conjugate, AZD8205, Alone and in Combination with the PARP1-Selective Inhibitor AZD5305.

PURPOSE: We evaluated the activity of AZD8205, a B7-H4-directed antibody-drug conjugate (ADC) bearing a novel topoisomerase I inhibitor (TOP1i) payload, alone and in combination with the PARP1-selective inhibitor AZD5305, in preclinical models. EXPERIMENTAL DESIGN: IHC and deep-learning-based image analysis algorithms were used to assess prevalence and intratumoral heterogeneity of B7-H4 expression in human tumors. Several TOP1i-ADCs, prepared with Val-Ala or Gly-Gly-Phe-Gly peptide linkers, with or without a PEG8 spacer, were compared in biophysical, in vivo efficacy, and rat toxicology studies. AZD8205 mechanism of action and efficacy studies were conducted in human cancer cell line and patient-derived xenograft (PDX) models. RESULTS: Evaluation of IHC-staining density on a per-cell basis revealed a range of heterogeneous B7-H4 expression across patient tumors. This informed selection of bystander-capable Val-Ala-PEG8-TOP1i payload AZ14170133 and development of AZD8205, which demonstrated improved stability, efficacy, and safety compared with other linker-payload ADCs. In a study of 26 PDX tumors, single administration of 3.5 mg/kg AZD8205 provided a 69% overall response rate, according to modified RECIST criteria, which correlated with homologous recombination repair (HRR) deficiency (HRD) and elevated levels of B7-H4 in HRR-proficient models. Addition of AZD5305 sensitized very low B7-H4-expressing tumors to AZD8205 treatment, independent of HRD status and in models representing clinically relevant mechanisms of PARPi resistance. CONCLUSIONS: These data provide evidence for the potential utility of AZD8205 for treatment of B7-H4-expressing tumors and support the rationale for an ongoing phase 1 clinical study (NCT05123482). See related commentary by Pommier and Thomas, p. 991.