AZD5582 / AstraZeneca - LARVOL DELTA

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

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

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

High TNF and NF-ĸB pathway dependency are associated with AZD5582 sensitivity in OSCC via CASP8-dependent apoptosis. (PubMed, Cancer Res Commun) - "CASP8-dependent apoptotic and CASP8-independent necroptotic cellular programs mediate AZD5582-induced cell death. In summary, through the systematic integration of pharmacological and CRISPR data, we identified a subset of OSCC with potent sensitivity to AZD5582 mediated through the NF-κB and TNF signalling pathways."

Journal • Oncology • Oral Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CASP8 • MAP3K7 • RNF31 • TNFA

Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal. (PubMed, bioRxiv) - "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 towards inducing HIV-1 reactivation. Moreover, knockout of INTS12 increased HIV-1 reactivation in CD4 T cells from virally suppressed PLWH ex vivo . We also 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."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

PD-1 blockade combined with therapeutic vaccination leads to sustained suppression of SIV following anti-retroviral therapy discontinuation in macaques (AIDS 2024) - "All RMs received five weekly IV infusions of AZD5582 from weeks 52 to 56 under ART as an LRA after the 1st MVA... These results showed that a combination of vaccination during ART and PD-1 blockade post ATI can achieve a functional cure for SIV in the presence of a potent anti-viral CD8 T cell response. These results have important implications for HIV cure."

Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8 • GZMB • IGFBP7

TARGETING PATIENT-SPECIFIC VULNERABILITIES IN ANTI-APOPTOTIC PATHWAY COMBINED WITH CXCR4 EXPRESSING CAR-T CELLS ELIMINATES HIGH-RISK LEUKEMIA. (EHA 2024) - "As informed by in vitro sensitivity, we performed in vivo treatment with AZD5582 and/or venetoclax-basedcombination treatment using PDX (patient-derived xenograft) models. Altogether, our precision medicine strategy targeting patient-specific anti-apoptotic proteins and cell surfaceantigens may improve clinical outcome in poor prognosis ALL, MPAL and CML."

CAR T-Cell Therapy • Clinical • IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • AURKB • BCL2 • CD7 • CXCL12 • CXCR4 • IL10 • IL2 • KRAS • MCL1 • TP53

KDM5A/B contribute to HIV-1 latent infection and survival of HIV-1 infected cells. (PubMed, Antiviral Res) - "In addition, we identified that the combination of JQKD82 and AZD5582, a non-canonical NF-κB activator, generates a synergistic impact on inducing HIV-1 lytic reactivation and cell death in the T cell...In latently infected microglia (HC69) of the brain, either deletion or inhibition of KDM5A/B results in a reversal of the HIV-1 latency. Overall, we concluded that KDM5A/B function as a host repressor of the HIV-1 lytic reactivation and thus promote the latency and the survival of HIV-1 infected reservoirs."

Journal • Human Immunodeficiency Virus • Infectious Disease • KDM5A

HIV Infection and Reactivation Heterogeneity in Tonsillar and Intestinal Models of HIV Persistence (CROI 2024) - "Intestinal latently infected CD4+ T cells exhibited greater reactivation with IL15 and AZD5582; whereas the tonsillar reservoirs responded better to ingenol (ING) and the combination of ingenol and romidepsin (ING+RMD). In our tonsillar and intestinal tissue models of HIV persistence, CD4+ T cell populations exhibited varying susceptibility to viral infection and reactivation, showing significant differences between tissues. Further research is required to identify LRAs effective against distinct HIV cellular reservoirs within these tissues."

Heterogeneity • Human Immunodeficiency Virus • Infectious Disease • CD4 • IL15

CD4-Targeted mRNA Delivery of Tat Reverses HIV-1 Latency (CROI 2024) - "Five J-Lat clones were treated with Tat mRNA-LNPs or small molecule agents (romidepsin, prostratin, pabinostat, or AZD5582) and evaluated using flow cytometry, live cell imaging, or single cell multiomic (RNA+ATAC) profiling. Ibalizumab (anti-CD4) was conjugated to mRNA-LNPs to generate CD4-targeted mRNA-LNPs...CD4-targeted Tat mRNA-LNPs selectively drive viral gene expression without cytotoxicity. These findings show that viral transcriptional programs, such as latency, can be modified using cell-targeted mRNA gene therapy."

IO biomarker • Gene Therapies • Human Immunodeficiency Virus • Infectious Disease • ANXA5 • CD38 • CD4 • CD69 • CD9 • IL2RA • MTRNR2L12 • SNHG5

Monovalent and Bivalent SMAC Mimetics Reverse HIV Latency and Decreases the HIV Reservoir (CROI 2024) - "Here we investigated whether monovalent and bivalent SMACm could reverse latency and/or deplete the reservoir.Latency reversal by monovalent (GDC0197, GDC0152, LCL161, Xevinapant) and bivalent (AZD5582, BV6) SMACm was assessed in J-Lat 10.6 cells (flow cytometry for GFP expression); the dual-reporter primary CD4+ T cell latency model Morpheus (flow cytometry for productive marker mCherry); and ex vivo CD4+ T cells from PLWH on ART (using HIV transcriptional profiling by digital PCR). Bivalent SMACm can reactivate latent HIV and deplete the reservoir. Monovalent SMACm although less potent in latency reversal, may have a novel role in enhancing clearance of the reservoir through altering antigen presentation and inducing greater CD8+ T cell mediated killing."

Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8

Vaccination Combined With PD-1 Blockade Provides Sustained SIV Suppression in Mamu-A01(+) Macaques (CROI 2024) - "A combination of vaccination during ART and PD-1 blockade post ATI can achieve a sustained functional cure for SIV in the presence of a potent anti-viral CD8 T cell response. These results also highlight the need for optimization of AZD5582 treatments in conjunction with vaccination to prevent the loss of vaccine-induced CD8 T cells."

Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8 • GZMB • IGFBP7

Treatment With AZD5582 + hetIL-15 Disrupts the Reservoir Establishment in SIV-Infected Macaques (CROI 2024) - "Altogether, these findings suggest that treatment with AZD5582, alone or in combination with hetIL-15, may reduce the size of virus reservoir when administered at the time of ART initiation during acute SIV infection, thus suggesting a disruptive effect on the reservoir establishment. These data are consistent with previous work on the latency reversing activity of AZD5582 and provides rationale for further exploring this compound as a curative agent for HIV infection."

Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8 • GZMB • IL15

Therapeutic potential of SHCBP1 inhibitor AZD5582 in pancreatic cancer treatment. (PubMed, Cancer Sci) - "Mechanistically, we found that AZD5582 induced the apoptosis of PC cells by inhibiting the activity of PI3K/AKT signaling and preventing the degradation of TP53. Collectively, our study highlights SHCBP1 as a potential therapeutic target and its inhibitor AZD5582 as a viable agent for PC treatment strategies."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • TP53

Simultaneous XIAP and cIAP1/2 inhibition by a dimeric SMAC mimetic AZD5582 induces apoptosis in multiple myeloma. (PubMed, J Pharmacol Sci) - "In multiple myeloma (MM), the IAP inhibitors (IAPi), LCL161, have been evaluated in preclinical and clinical settings but are not fully effective...AZD5582 combined with carfilzomib therapy showed a synergistic effect...Simultaneous XIAP and cIAP1/2 inhibition by the dimeric IAPi AZD5582 is promising. This study provides a rationale of AZD5582 as a new treatment strategy in monotherapy and in combination therapy."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • BIRC3 • IL6 • XIAP

Optimized lipopolymers with curcumin to enhance AZD5582 and GDC0152 activity and downregulate inhibitors of apoptosis proteins in glioblastoma multiforme. (PubMed, Biomater Adv) - "Surface FA, Lf and RVG also promoted the ability of the drug-loaded LPs to avoid carcinoma growth. The current FA-, Lf- and RVG-crosslinked LPs carrying AZD, DGC and CURC can be promising in hindering IAP expressions for GBM management."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CASP3 • XIAP

Mycoplasma hyorhinis infection promotes TNF-α signaling and SMAC mimetic-mediated apoptosis in human prostate cancer. (PubMed, Heliyon) - "Tissue microarray analysis indicated that TNF-α is co-expressed in M. hyorhinis-infected human patient tissues. Findings from this study advance our understanding of the mycoplasma-oncogenesis process and suggest the potential for new approaches for preventions, diagnosis, and therapeutic approaches against prostate cancers."

Journal • Genito-urinary Cancer • Infectious Disease • Oncology • Prostate Cancer • Solid Tumor • TNFA

EXPRESS: cIAP1/2 can regulate the inflammatory response and lung injury induced by apoptosis in septic rats. (PubMed, J Investig Med) - "Inhibiting cIAP1/2 with AZD5582, a second mitochondrial-derived activator of caspases (SMAC) mimetic, induced increased apoptosis and reduced lung injury. Therefore, inhibiting cIAP1/2 can alleviate sepsis-induced ALI, providing a new target for regulating organ damage induced by sepsis-induced inflammatory responses."

Journal • Preclinical • Acute Lung Injury • Acute Respiratory Distress Syndrome • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • Septic Shock • Targeted Protein Degradation • BIRC2

AZD5582 plus SIV-specific antibodies reduce lymph node viral reservoirs in antiretroviral therapy-suppressed macaques. (PubMed, Nat Med) - "Here we confirm the efficacy of AZD5582 in inducing SIV reactivation, demonstrate enhancement of latency reversal when AZD5582 is used in combination with N-803 and show a reduction in total and replication-competent SIV-DNA in lymph-node-derived CD4 T cells in macaques treated with AZD5582 + RhmAbs. Further exploration of this therapeutic approach may contribute to the goal of achieving an HIV cure."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4