AZD5582 / AstraZeneca - LARVOL DELTA

T-cell responses shape infant SIV reservoirs and post-intervention control following AAV9-eCD4-Ig and latency reversal. (PubMed, JCI Insight) - "Controllers also exhibited higher frequencies and greater polyfunctionality of virus-specific CD8+ T-cells prior to ATI. These findings implicate immune control of reservoir size and post-ART viral dynamics in early-treated infants and suggest that AAV9-eCD4-IgG1 + AZD5582 increases the likelihood of post-ART viral control."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8

Non-genetic remodeling drives leukemia propagation and reveals actionable vulnerabilities in acute myeloid leukemia. (PubMed, Cell Rep Med) - "A pharmacological screen of 3,247 compounds uncovers a limited set of vulnerabilities that consistently emerge during disease progression, including CRBN-dependent degradation of GSPT1 (CC-885) and IAP antagonism (AZD5582). In vivo validation shows that both agents markedly reduce leukemic burden, impair leukemia propagation, and enhance cytarabine activity in patient-derived xenograft (PDX) models. Together, these findings show that leukemic propagation is driven by a non-genetic remodeling program, providing a framework to prioritize and test stage-specific therapeutic strategies in AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • CRBN • GSPT1

Interaction between p-AMPK and RIPK3 reveals a mechanism by which AdipoAI suppresses necroptosis to attenuate periodontitis. (PubMed, J Transl Med) - "This study is the first to unveil a mechanism by which AdipoAI suppresses GF necroptosis through p-AMPK-mediated RIPK3 regulation, offering new strategic insights and experimental evidence for targeted periodontitis therapy."

Journal • Dental Disorders • Inflammation • Periodontitis

A Three-Gene Prognostic Signature Driven by an ER Stress-Associated ceRNA Network: Integrating Single-Cell Transcriptomics and Cross-Platform Validation in Hepatocellular Carcinoma. (PubMed, Curr Issues Mol Biol) - "Drug sensitivity analysis indicated that the high-risk group was more sensitive to drugs such as docetaxel and AZD5582, consistent with the upregulation of proliferation pathways in this group; in the low-risk group, VE-822 exhibited selective sensitivity. This study established a three-gene prognostic signature based on the ERS-associated ceRNA network. The signature demonstrated robust prognostic stratification capabilities in cross-platform validation and revealed molecular characteristics centered on uncontrolled cell-cycle progression, as well as an immunosuppressive microenvironment, in the high-risk group, providing an exploratory tool for prognostic assessment and treatment strategy selection in hepatocellular carcinoma (HCC)."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • ATF3 • CCL2 • CKS1B • PSAT1 • STC2

Blocking Host Factors IAP and DDX3 Activates HIV-1 Transcription and Increases Apoptosis Sensitivity of HIV-1 Infected Cells. (PubMed, Pathogens) - "Inhibition of IAP by second mitochondrial-derived activator of caspases mimetic (SMACm; AZD5582) resulted in activation of non-canonical NF-κB pathway (RelB/p52) that induced HIV-1 transcription, confirming previous reports, whereas inhibition of DDX3 sensitized HIV-1 infected cells for apoptosis (DDX3i; FH1321)...Notably, DDX3 inhibition specifically restored the expression of the majority of HIV-1 suppressed genes, and when combined with SMACm, restored almost all HIV-1 downregulated genes, thereby rendering HIV-1 infected cells sensitive to apoptosis. Thus, our data strongly suggest that inhibition of host factors IAP and DDX3 not only induces activation of HIV-1 transcription but also restores HIV-1 suppressed apoptotic processes in infected cells."

Journal • Human Immunodeficiency Virus • Infectious Disease

AZD5582 robustly reactivates latently infected cells and clears the majority of those reactivated from the SIV reservoir. (PubMed, bioRxiv) - "Future work should focus on improving LRAs that safely reactivate a larger fraction of the latent reservoir. Furthermore, designing experiments with varying dosing schedules can help better quantify the duration of refractoriness, which will be important for informing optimal treatment schedules and maximizing the effect of LRAs."

Journal • Human Immunodeficiency Virus • Infectious Disease

AZD5582-reactivated cells likely differ from productively infected cells (IMMUNOLOGY 2026) - "Detailed analysis of the mechanisms is difficult to study due to low amplitude and fluctuating viral load signals. We analyzed longitudinal data from 29 ART-suppressed, SIV-infected rhesus macaques treated with AZD5582 in combination with other agents (e.g., SIV antibodies, N-803, and/or MT807R1). Mechanistic modeling provides an explanation for the limited reduction in the viral reservoir despite the strong latency reversal achieved by AZD5582. The model revealed that reactivated cells behave differently from fully productively infected cells. This finding suggests that combining AZD5582 with other type of latency reversing treatment may improve the overall effectiveness and robustness of the drug."

BIRC3/CAV1 co-expression drives GBM aggressiveness as a prognostic signature and therapeutic vulnerability. (PubMed, Cell Death Discov) - "Glioblastoma (GBM) is an incurable tumor where temozolomide (TMZ) resistance limits survival, even in MGMT-methylated patients. Importantly, BIRC3/cIAP2-driven resistance proved targetable; the IAP antagonist AZD5582 restored TMZ sensitivity by unlocking the apoptotic execution phase, thereby inducing cell death in resistant GBM models in vitro and ex vivo. Our findings establish the BIRC3/CAV1 axis as a key prognostic signature and therapeutic vulnerability in GBM, offering a new path for precision oncology strategies."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • BIRC3 • CAV1 • MGMT

Development and validation of a ferroptosis-related gene signature for prognostic prediction and therapeutic target identification in invasive lobular carcinoma. (PubMed, Transl Cancer Res) - "Sensitivity analysis and molecular docking revealed that KLRB1 and SERPINB5 are hypothesis-generating targets and that rapamycin and AZD5582 are hypothesis-generating drug candidates for the treatment of ILC. By integrating multi-omics analysis, machine learning and molecular docking, we established a robust prognostic model for ILC, revealed two distinct ferroptosis-related molecular subtypes, and identified potential therapeutic targets and candidate drugs. These findings may help advance the development of personalized medicine and targeted therapies for ILC."

Gene Signature • Journal • Breast Cancer • Oncology • Solid Tumor • KLRB1 • SERPINB5

IAP Antagonists Selectively Eliminate Therapy-Induced Senescent Cancer Cells via TNFα-Independent Apoptosis. (PubMed, Cancer Sci) - "Here, we show that AZD5582 and AT406, potent antagonists of cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1 and cIAP2) and X-linked inhibitor of apoptosis protein (XIAP), selectively eliminated HCT116 and RKO cells that had undergone senescence following treatment with a chemotherapeutic agent such as trifluridine, camptothecin, or doxorubicin. At physiological concentrations, TNFα sensitized non-senescent, proliferating cancer cells, but not TIS and nutlin-3a-induced senescent cancer cells, to apoptosis in the presence of IAP antagonists. Collectively, these findings suggest that IAP antagonists could serve as effective concomitant agents to TIS-inducing chemotherapy that promotes TNFα secretion within tumors, functioning not only as TNFα-independent senolytics but also as potentiators of TNFα-mediated apoptosis in adjacent non-senescent, proliferating cancer cells."

Journal • Oncology • BIRC3 • CASP8 • TNFA • XIAP

Identification of inducible HIV reservoirs in tonsillar, intestinal and cervical tissue models of HIV latency. (PubMed, Nat Commun) - "Furthermore, using different latency reversal agents (LRAs) demonstrates that Histone Deacetylase Inhibitors (HDACis) fail to induce HIV in any tissue, the SMAC mimetic AZD5582 is effective only in a resident-memory CD4+ T-cell subpopulation in the intestine, and IL-15 exhibits the broadest reactivation potential across tissues and CD4+ T-cell subsets. These models provide insights into the inducible reservoir's composition in different tissues and inform strategies for its elimination."

IO biomarker • Journal • Human Immunodeficiency Virus • Infectious Disease • CCR7 • CD69 • CXCR5 • IL15 • ITGA1 • PD-1

Combined Targeting Patient-Specific Anti-Apoptotic Molecules and CXCR4-Expressing CAR-T Cells Eliminated High-Inflammation State Leukemia with Poor-Prognostic Mutations (ASH 2024) - "We found high responsiveness of T-ALL/MPAL to venetoclax (88.9%, eight out of nine samples) and high sensitivity to BIRC inhibitor (AZD5582) in CML (83.3%, 10 out of 12 samples). Reduction of leukemia burden followed by CXCR4 CAR-T cells eradicated leukemic cells in bone marrow and spleen without severe cytokine release syndrome. Altogether, our patient-specific therapeutic strategy may contribute to precision medicine approach and improve clinical outcome in poor prognosis leukemia."

CAR T-Cell Therapy • Clinical • IO biomarker • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • ABL1 • AURKB • BCL2 • BCR • CD7 • CXCL12 • CXCR4 • KMT2A • KRAS • TP53

POWER DUO: UNLEASHING THE SYNERGY OF IAP INHIBITORS WITH INOTUZUMAB OZOGAMICIN IN TP53 DEFICIENT ACUTE LYMPHOBLASTIC LEUKEMIA (SIOP 2025) - "A high-throughput drug screen identified IAP inhibitors AZD5582 and Birinapant as a powerful sensitizers of the response to InO in TP53 KO cells. We compared the effects of AZD5582 on the response to InO with the clinical stage Bcl2 inhibitor venetoclax, finding that IAP inhibitors strongly outperform this Bcl2 inhibitor in TP53 deficient ALL. Conclusions Our findings indicate that combining IAP inhibitors with Inotuzumab Ozogamicin could restore therapy response to InO in patients with TP53 deficient ALL."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Pediatrics • T Acute Lymphoblastic Leukemia • CASP3 • CASP7 • CASP9

Integrated single-cell and bulk RNA-sequencing data reveal prognosis and therapeutic response in low-grade glioma based on hypoxia-lactylation related genes. (PubMed, Discov Oncol) - "The constructed 4-gene hypoxia-lactylation prognostic model can effectively predict survival risk in LGG patients. The high-risk group is characterized by activation of pro-tumorigenic pathways, high immune infiltration, and sensitivity to specific targeted drugs. FABP5 + TAMs participate in LGG progression by regulating lipid metabolism and inflammatory responses, representing a potential therapeutic target."

Journal • Brain Cancer • Glioma • Metabolic Disorders • Oncology • Solid Tumor • FABP5 • KIF2C • SERPINE1 • SLC16A1

Methylseleninic acid enhances HIV reactivation induced by other latency reversing agents (IAS-HIV 2025) - "We explored whether the organic selenium compound Methylseleninic acid (MSA), an activator of transcription of the transcription factor BMAL-1 that drives HIV long terminal repeat (LTR) mediated viral transcription, could synergise with other known latency reversing agents (LRA). CD4+ T-cells isolated from peripheral blood mononuclear cells from PLWH on ART were cultured with MSA alone, or in combination with the SMAC mimetic, AZD5582; bromodomain inhibitor, JQ1; or protein kinase C (PKC) agonist, PEP005 for 48 hours. MSA synergised with SMACm AZD5582 and PKC agonist PEP005, enhancing latency reversal in primary CD4+ T-cells from PLWH. MSA represents a novel approach to enhance latency reversal."

Human Immunodeficiency Virus • Infectious Disease • ARNTL • CD4

Unique cellular signatures and HIV transcripts identified in CD4 lymphoid T cells - HOPE Act organ transplantation collaboration (IAS-HIV 2025) - "For transcriptional changes following LRA treatment, CD4+ T cells were isolated from lymph nodes in 6/24 samples and were stimulated for 24 hours with LRA combinations (VOR+AZD5582, VOR+AZD5582+IL-15 and VOR+AZD5582+IL-15+iBet-151) prior to single cell RNA sequencing (scRNAseq). Using scRNA analysis of a total 94,716 cells we identified 57 cells with HIV transcripts most of which mapped to viral LTR. Lymph nodes obtained from PLWH undergoing solid organ transplantation represent a high yield source for deep lymphatic tissue. We identified LRA-induced HIV reactivation and defined effects of LRA combinations on transcriptomic profiles of tissue resident CD4 T cells. This data can be used to evaluate future LRAs and assess their combination efficacy and their ability to unmask the lymphatic reservoir."

Human Immunodeficiency Virus • Infectious Disease • Solid Organ Transplantation • Transplantation • CD4 • IL15

Exosomal delivery of AZD5582 to overcome TRAIL resistance as an optimal therapy against triple-negative breast cancer. (PubMed, Acta Histochem) - "It also demonstrated significant potential for treating kidney cancer in A498 kidney tumor organoids. Together, AZD@EV-T effectively overcomes TRAIL resistance and may represent a highly effective and innovative anticancer therapy for both TNBC and kidney cancers."

Journal • Breast Cancer • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Triple Negative Breast Cancer • TNFA • TNFRSF10B

Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal. (PubMed, Elife) - "Combining latency reversal agents (LRAs) with differing mechanisms of action such as AZD5582, a non-canonical NF-kB activator, and I-BET151, a bromodomain inhibitor is appealing toward inducing HIV-1 reactivation. Moreover, knockout of INTS12 increased HIV-1 reactivation in CD4 T cells from virally suppressed PLWH ex vivo, and we detected viral RNA in the supernatant from CD4 T cells of all three virally suppressed PLWH tested upon INTS12 knockout, suggesting that INTS12 prevents full-length HIV RNA production in primary T cells. Finally, we found that INTS12 more generally limits the efficacy of a variety of LRAs with different mechanisms of action."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

AZD5582 and Venetoclax Reduce SIV Reservoirs in ART-Suppressed Macaques (CROI 2025) - "Conclusions The combination of AZD5582 and VTX reduced the intact SIV reservoir in peripheral blood and bone marrow but did not delay viral rebound after ATI. These findings highlight the intricate relationship between latency reversal, reservoir size, and viral rebound."

Human Immunodeficiency Virus • Infectious Disease • CD4

Convergence of NF-κB Pathways Increases HIV-1C Transcriptional Fitness (CROI 2025) - "Methods Jurkat cells were treated with AZD5582 to selectively activate the alternative NF-kB pathway...Conclusions In conclusion, our results suggest that HIV-1C LTR integrates both classical and alternative NF-kB signals more effectively than HIV-1B, contributing to its transcriptional superiority and replication fitness. Future research will assess clinical samples to further compare HIV-1B and HIV-1C LTR responses, potentially informing novel strategies for HIV-1 latency reversal and cure."

Human Immunodeficiency Virus • Infectious Disease • CD4 • NFKBIA • TNFA

Combination of eCD4-IgG1 Delivered by AAV9 and AZD5582 in SIV-Infected, ART-Suppressed Infant RM (CROI 2025) - "Peak levels of on-ART viremia during AZD5583 treatment surpassed those observed in prior studies of adult RM. Further research is needed to elucidate the mechanisms behind post-rebound viral control in the intervention group."

Human Immunodeficiency Virus • Infectious Disease • CD4 • IGFBP7

AZD5582 Inhibits Vaccine-Elicited CD8+ T-Cell Responses in SIV-Infected Rhesus Macaques on ART (CROI 2025) - "Conclusions Collectively, these data suggests that AZD5582 diminished mRNA/SIV-Gag vaccine-induced CD8+ T cell responses and abrogated vaccine-enhanced early intercept of rebounding infections following ATI. This highlights the need for novel latency-reversal agents that do not disrupt the effector activity of CD8+ T cell responses."

Late-breaking abstract • Infectious Disease • CD8

The XIAP inhibitor AZD5582 improves the treatment effect of microwave ablation on hepatocellular carcinoma. (PubMed, Front Immunol) - "These results provide new clues for hepatocellular carcinoma treatment, suggesting the potential role of XIAP inhibitors in hepatocellular carcinoma treatment and their impact in immunomodulation. In this study, we found that the XIAP inhibitor AZD5582 modulates the immune microenvironment and inhibits the progression of post-ablation residual hepatocellular carcinoma."

Journal • Hematological Disorders • Hepatocellular Cancer • Hepatology • Immunology • Liver Cancer • Oncology • Solid Tumor • CD8 • FOXP3 • XIAP

Integrated mRNA-seq and miRNA-seq analysis reveals key transcription factors of HNF4α and KLF4 in ADPKD. (PubMed, Biochem Biophys Res Commun) - "Drug response prediction analysis revealed potential drug candidates for ADPKD treatment, including BI-2536, Sepantronium, and AZD5582. This integrated analysis provides new epigenetic insights into the complex miRNA-TF-mRNA network in ADPKD and identifies HNF4α and KLF4 as key TFs. These findings offer valuable resources for further research and potential drug development for ADPKD."

Journal • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • KLF4 • PKD1 • PRKD1

Combination cIAP and BCL-2 inhibition reduces intact reservoirs in ART-suppressed SIV-infected rhesus macaques (HIVR4P 2024) - "Here we investigated a synergistic strategy using the cIAP-inhibitor AZD5582 and the BCL-2 inhibitor Venetoclax (VTX) to reverse latency and enhance the apoptosis-mediated clearance of reactivated infected CD4+ T cells. Thirty SIVmac239M-infected rhesus macaques (RMs) were initiated on ART at 4 weeks post-infection (wpi). The combination of AZD5582 and VTX had a favorable effect in reducing the level of blood and bone marrow CD4+ T cells with intact SIV DNA in ART-suppressed RMs. This reduction was insufficient to modulate viral rebound dynamics during ART interruption, underscoring the challenge of eliminating rebound-competent reservoirs in established SIV/HIV infections."

Late-breaking abstract • Human Immunodeficiency Virus • Infectious Disease • CD20 • CD4