birinapant (IGM-9427) / University of Pennsylvania, Medivir, IGM Biosciences - LARVOL DELTA

Birinapant enhances cisplatin sensitivity in epithelial ovarian cancer through modulation of apoptotic and survival signaling pathways. (PubMed, Cancer Chemother Pharmacol) - "Birinapant increased the sensitivity of SKOV3 ovarian cancer cells to cisplatin by enhancing TNF-α-associated apoptotic signaling, while this synergistic effect was not observed in MDAH-2774 cells, emphasizing the importance of cellular context in determining SMAC mimetic responses. Our findings suggest that TNF-α responsiveness, cIAP1 (BIRC2)-related signaling, and the ability of cancer cells to activate apoptotic pathways, particularly caspase-8, may serve as potential biomarkers for identifying tumors more likely to respond to Birinapant-based combination therapies. Further studies using additional ovarian cancer models and clinical samples are required to validate the predictive value of these biomarkers."

Journal • Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • ANXA5 • BIRC2 • CASP3 • CASP8 • RELA • TNFA

Multiscale modeling uncovers macrophage infiltration and TNF-α signaling networks for targeting in inflammatory breast cancer tumor emboli. (PubMed, Breast) - "This study, the first to our knowledge, identifies TNF-α signaling and macrophage infiltration in IBC tumor emboli. Therapeutic strategies targeting TNF-α signaling to induce cell death and reduced macrophage influence have the potential to improve IBC outcomes."

Journal • Breast Cancer • Inflammatory Breast Cancer • Oncology • Solid Tumor • CD163 • CX3CR1 • CXCL8 • TNFA

Inhibitors of IAP/XIAP enhance activity of sacituzumab govitecan. (PubMed, J Natl Cancer Inst) - "In PDXs, birinapant enhanced the antitumor activity of several chemotherapeutics, especially irinotecan, a metabolic precursor of payload SN-38. We subsequently demonstrated that combinations of SG with birinapant or tolinapant had greater antitumor activity and significantly prolonged event-free survival compared with SG alone. In vitro, IAP antagonists significantly synergized with SG on inhibition of cell viability and colony formation, and on apoptosis induction. These findings suggest that SG combination with IAP inhibitors may represent an effective therapeutic strategy for breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • XIAP

Birinapant and Intensity Modulated Re-Irradiation Therapy in Treating Patients With Locally Recurrent Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P1 | N=13 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jul 2026 ➔ Jul 2027

Trial completion date • Tumor mutational burden • Head and Neck Cancer • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Species, cell proliferation state and oxygen partial pressure are major factors in the in vitro toxicity of repurposed potential ADPKD drugs in human and murine renal proximal tubule cells. (PubMed, Arch Toxicol) - "In a quest for potential alternatives to tolvaptan, we compared the nephrotoxic and metabolic effects of four repurposed drugs, salicylic acid (up to 10 mM), birinapant (up to 100 µM), bardoxolone methyl (up to 1000 nM), and rapamycin (up to 160 nM) to tolvaptan (up to 100 µM) on human differentiated and proliferating (RPTEC/TERT1) and mouse proliferating (mProx24) renal proximal tubular epithelial cells at atmospheric (21%) and physiological (10%) O2 tensions. The focus was on improved interpretation of in vitro test results for the detection of potential adverse effects. We found that cell proliferation and O2 tension are major factors that determine the susceptibility of cells to compounds, while the drug effects on the metabolism and mitochondrial function provided further insight into the mechanisms underlying the observed in vitro toxicity."

Journal • Preclinical • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Comprehensive Pan-Cancer Bioinformatics Analysis Identifies DHX58 as a Promising Therapeutic Target and Prognostic Biomarker Across Multiple Tumor Types. (PubMed, Asian Pac J Cancer Prev) - "Our pan-cancer analysis reveals that DHX58 has context-specific prognostic and predictive roles. While discrepancies between platforms exist, DHX58 emerges as a potential biomarker in specific cancers, particularly in the context of therapies involving agents like birinapant. These findings warrant further mechanistic and clinical investigation."

Biomarker • Journal • Pan tumor • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Chemotherapy primes tumor-associated macrophages to enable caspase-8 dependent apoptosis triggered by birinapant in ovarian cancer cells (EACR 2026) - "Promising combinations, including the SMAC mimetic-birinapant with carboplatin, were validated in ex vivo patient-derived HGSC cultures and syngeneic mouse models, with tumor-associated macrophages (TAMs) dependence assessed via macrophage depletion. Chemotherapy primes the tumor microenvironment by increasing TNFα expression primarily in TAMs, enabling birinapant to trigger apoptosis in HGSC cells. Sequential birinapant administration following chemotherapy may enhance treatment responses in chemoresistant tumors. Furthermore, elevated TNFα levels and higher TAM abundance could serve as surrogates for treatment stratification."

High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • CASP3 • CASP8 • TNFA

Palbociclib and birinapant exert synergistic anti-tumor efficacy in triple-negative breast cancer – a preclinical analysis of a promising drug combination (DGS 2026) - "These changes rendered the cells more susceptible to apoptosis activation by birinapant. The CDK4/6 inhibitor palbociclib in combination with the SMAC mimetic birinapant demonstrated synergistic anti-tumor efficacy in a preclinical TNBC model."

Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BIRC5 • CASP8 • TNFRSF10B

DGS Science Prize: Palbociclib and birinapant exert synergistic anti-tumor effect in triple-negative breast cancer - a preclinical analysis of a promising drug combination (DGS 2026) - No abstract available

Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Identification of drug repurposing candidates for the treatment of polycystic kidney disease. (PubMed, Br J Pharmacol) - "We have identified novel targets of three repurposing candidates that contribute to the cyst growth reducing effects in preclinical ADPKD models and identify salicylic acid, the metabolite of aspirin, as the repurposing candidate with the most promising mechanisms of action."

Journal • Autosomal Dominant Polycystic Kidney Disease • Chronic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Co-morbid biomarkers for sarcopenic obesity associated with gut microbiota metabolites: From burden to treatment. (PubMed, PLoS Comput Biol) - "ALDH1A3, CSF1R, and PHGDH serve as potential co-morbid biomarkers for SO."

Biomarker • Journal • Genetic Disorders • Obesity • Sarcopenia • ALDH1A3 • CSF1R • PHGDH

Time-Resolved Transcriptomic Profiling of Surgical Wounds Identifies Stage-Specific Therapeutic Targets for Residual Ovarian Cancer. (PubMed, Pharmaceutics) - "At T1, WsDEGs were enriched in inflammatory signaling, coagulation, angiogenesis, and immune cell migration, with Vorinostat and Homoharringtonine identified as top candidates to counteract these signatures. At T2, pathways related to cell survival, adhesion, and morphogenesis predominated, with LY-2090314, Artesunate, and Birinapant emerging as potential modulators. At T3, cell-cycle regulation and lipid metabolic pathways were dominant, and Fulvestrant, Atorvastatin, Imatinib, and ABT-737 were predicted to inhibit these processes. Perioperative surgical wounding induces dynamic, stage-specific transcriptomic programs that may promote ovarian cancer progression and alter drug responsiveness. These findings support time-adapted perioperative pharmacologic strategies to optimize postoperative cancer therapy."

Journal • Anesthesia • Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor

Identifying novel therapies from unbiased screens in AML with MECOM re-arrangement (AACR 2024) - "Consistent with this, co-treatment of mivebresib with SMAC mimetic birinapant or IAP inhibitor LCL161 was synergistically lethal against 3q26.2-r cells. Co-targeting the other identified druggable vulnerabilities from the drug screen with BETi (mTOR/PI3K with BGT-226 and dactolisib, Bcl-xL with navitoclax and A1155463, as well as CBP/p300 (with GNE781, identified through the CRISPR screen), exerted synergistic lethality in 3q26.2-r AML cells...These findings demonstrate promising preclinical activity of BETi and IAP protein or mTOR/PI3K antagonists in the cellular models of AML with EVI1 overexpression. This supports the rationale to determine in vivo efficacy of these BETi-based combinations against this therapy-resistant AML sub-type."

Acute Myelogenous Leukemia • Oncology • BCL2L1 • BRD4 • CASP3 • CDK4 • HEXIM1 • MCL1 • MECOM • mTOR • MYC • PIK3CA • XIAP

Evaluating TNF-receptor associated factor 2 (TRAF2) as a targetable driver of immune resistance in LKB1 deficient non-small cell lung cancer (AACR 2024) - "This showed that inhibition of cIAP1 using birinapant was synergistic to CD8 cytotoxicity, as previously known, but the synergy was much more pronounced in STK11 mutant vs STK11-WT context (Bliss index 38, P<1e-10). Together, these data demonstrate that the link between STK11-loss and cIAP1 dysregulation is likely through over-expression of TRAF2, and support the strategy of targeting TRAF2/cIAP1 to overcome immune resistance STK11-deficient NSCLC."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AMPK • CD8 • KRAS • STK11

Tumor-extrinsic BIRC3 promote sensitivity to checkpoint inhibition immunotherapy in breast cancer (AACR 2024) - "Birinapant, a selective BIRC3 inhibitor, was then used to investigate the effect of BIRC3 blockade on tumor immune microenvironment (TIME) landscape of breast cancer syngeneic mouse models by flow cytometry...Our study revealed a positively association between BIRC3 and anti-tumor immune landscape in breast cancer. Notably, we established a validated prognosis model based on BIRC3 and BIRC3 associated immunomodulators in breast cancer."

Checkpoint inhibition • IO biomarker • Breast Cancer • Oncology • Solid Tumor • BIRC3 • CD8

BIRC3 and NOC2L synergistically promote P53 acetylation to accelerate necroptosis in sepsis-associated acute kidney injury. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "Meanwhile, Birinapant, an inhibitor of BIRC3, attenuated necroptosis and inflammatory responses...Furthermore, BIRC3 and its interacting protein NOC2L synergistically regulate p53 acetylation, thereby promoting downstream necroptosis. BIRC3 and NOC2L may serve as potential therapeutic targets for SA-AKI, offering novel therapeutic strategies."

Journal • Acute Kidney Injury • Infectious Disease • Inflammation • Nephrology • Renal Disease • Septic Shock • ANXA5 • BIRC3

A monovalent SMAC mimetic as a potential host-directed therapy for tuberculosis. (PubMed, J Infect Dis) - "This study highlights BI82's unique apoptosis-dependent mechanism and broad-spectrum potential against mycobacterial infections, including drug-resistant TB, positioning it as a promising HDT candidate."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • CASP3 • CD4 • CD8

SMAC mimetics sensitize HIV-infected cells to oncolytic virus-mediated death. (PubMed, Front Immunol) - "As small-molecule second mitochondria-derived activator of caspases (SMAC) mimetics have been shown to increase OV-mediated death in cancer models, we used the SMAC mimetics LCL-161 and birinapant alongside MG1 to enhance the killing of HIV-infected cell lines and monocyte-derived macrophages (MDMs). This cell death occurs via both caspase-dependent and caspase-independent mechanisms and is not completely dependent on tumor necrosis factor alpha (TNFα). Together, these results show that the use of SMAC mimetics alongside OVs may be a viable strategy to eradicate latently/persistently HIV-infected cells."

Journal • Human Immunodeficiency Virus • Infectious Disease • Oncology • TNFA

Understanding resistance to the SMAC mimetic birinapant in triple-negative breast cancer (SABCS 2025) - "Using PDxOs, inability to execute TNFR-mediated apoptosis signaling was identified as a mechanism of birinapant-resistance in TNBC. This regulation protects TNBC tumors from birinapant-induced cell death and is likely protective against all SMAC mimetics. These data suggest that identifying ways to overcome the failure to execute TNFR-mediated apoptosis signaling may expand the patient population that will benefit from birinapant treatment."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • TNFA

Tumor emboli in inflammatory breast cancer reveals macrophage-TNF-a signaling networks as targetable pathways (SABCS 2025) - "Using both preclinical models and patient-derived biospecimens, our research showed that IBC tumor emboli contribute to TAM infiltration in TiME, driving pro-survival TNFα-NFκB-XIAP signaling leading to drug resistance. We identified birinapant as a potential therapeutic agent to disrupt this signaling axis, which paves a path towards the development of new treatments for IBC."

Breast Cancer • Inflammatory Breast Cancer • Oncology • Solid Tumor • CCL20 • CX3CR1 • CXCL10 • IL6 • TNFA • XIAP

Integrated multiomics identifies inhibitors of apoptosis (IAPs) and death-inducing signaling complex (DISC) components as novel vulnerabilities to overcome immune evasion in TP53-inactivated Acute Myeloid Leukemia (ASH 2025) - "Notably, AML patients with TP53 mutations have limited benefit from standard inductionchemotherapy or from recently approved venetoclax-based combination regimens...We found that IAPinhibitors birinapant and tolinapant, as well as IAP PROTAC-degrader CST-626, potently sensitized TP53-inactivated AML to CAR-T/TCR-T and NK-92-mediated cytotoxicity...Pharmacological inhibition of thecaspase 8-cFLIP heterodimer with emricasan alone, or combined with IAP antagonists, effectivelyovercomes this checkpoint and sensitizes AML cells to immune cytotoxicity. These findings establish astrong preclinical rationale for combining cell death–promoting agents with T or NK cell–basedimmunotherapies to overcome immune resistance in TP53-mutated high-risk AML subset."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Targeted Protein Degradation • BIRC2 • BIRC3 • CASP8 • FADD • TP53 • XIAP

Comparative analysis of molecular targeted radiosensitizers in 2D and 3D cancer cell line models. (PubMed, Acta Oncol) - "Integrating multiple culture models enhances the detection of cell line - and drug-specific radiosensitization. Although 2D and 3D cultures produced largely similar results, and 2D assays provide a practical alternative when 3D methods are not feasible, the 3D cultures reveal additional ECM-dependent responses. These results emphasize the utility of physiologically relevant platforms for robust screening and prioritization of candidate radiosensitizers."

Clinical • Journal • Preclinical • Lung Cancer • Oncology • Solid Tumor

Actionable Findings from an Unbiased Drug Screen for Novel Single Agent and Combination Therapies Against AML with Mecom Re-Arrangement (ASH 2023) - "This was consistent with previous reports that BET inhibitors (e.g., OTX015, mivebresib or ABBV-075 and JQ1) are effective against 3q26.2-r AML cell lines, patient-derived (PD) AML cells and PDX models...In follow-up experiments, XIAP/cIAPs inhibitors birinapant (10-1000 nM) or SM-164 (30-1000 nM), chosen based on the MIPE screen outcomes, induced significantly more dose-dependent apoptosis in 3q26.2-r versus the other AML cell lines...Treatment with the dual mTOR/PIK3CA inhibitor NVP-BGT226 (1-30 nM) or navitoclax or Bcl-xL-specific BH3 mimetic A-1155463 also exerted lethality and synergistically induced apoptosis with mivebresib in AML cells with inv3/t(3; 3)...Co-treatment with birinapant and tegavivint also synergistically induced apoptosis in 3q26.2-r AML cells...Additionally, compared to each drug or vehicle control, co-treatment with birinapant and the BETi OTX015 (30 mg/kg/day, by oral gavage) was more effective in reducing AML burden in the xenograft model...."

Combination therapy • Acute Myelogenous Leukemia • Oncology • BCL2L1 • BRD4 • CASP3 • CDK4 • CTNNB1 • GATA2 • HEXIM1 • MCL1 • MECOM • MYC • PIK3CA • SF3B1 • XIAP

T-prolymphocytic leukemia(T-PLL) – What are recent improvements? (DGHO 2025) - "With the aim to further improve clinical outcomes, a prospective phase-II trial was conducted by the German CLL Study group using an induction therapy with fludarabine, cyclophosphamide and mitoxantrone (FMC) followed by alemtuzumab consolidation therapy...CIBMTR Data of 266 patients with T-PLL demonstrated a 4-year disease-free survival (DFS) of 25.7% and OS of 30.0%.There are recent clinical pilot data derived from drug screening efforts that provide valuable insights: venetoclax, HDAC-inhibition plus idasanutlin (MDM2 antagonist, activation of p53), and drugs targeting autophagy (thapsigargin and bafilomycin A1), nuclear export (selinexor) or inhibitor of apoptosis proteins (IAPs; birinapant). Valuable trial data teach us on the limited applicability of pre-clinical results, i.e. the limited efficacy of venetoclax+ibrutinib or of itacitinib + alemtuzumab.Overall, responses after induction therapy remain dissatisfactory as most patients relapse even after a CR..."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Prolymphocytic Leukemia

Targeting Mitochondrial Apoptotic Priming State to Personalize Therapy for Relapsed Acute Myeloid Leukemia (ASH 2023) - "We tested in vivo sensitivity to 5 drugs of disparate mechanisms of action: birinapant and LCL-161 (SMAC mimetics), JQ-1 (BRD-4 inhibitor), venetoclax (BCL-2 antagonist), and quizartinib (FLT-3 inhibitor) in 4-9 different PDX models each. Overall, we demonstrate that acquired resistance to targeted therapy in AML is accompanied by common mechanism of reduction in mitochondrial priming along with drug-specific resistance mechanisms. Further, we find that, even in the context of a multiply-resistant PDX model, DBP can still identify therapeutic vulnerabilities that can be efficaciously exploited in vivo."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BRD4 • FLT3 • PTPRC