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

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

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

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

Integrative Analysis of Transcriptomic and Proteomic Data Identifies Patterns of Primary Resistance to Venetoclax-Azacitidine and Reveals Targetable Vulnerabilities in Acute Myeloid Leukemia (AML) (ASH 2024) - "Results : In the BCL2 family inhibitor drug sensitivity assay, navitoclax (BCL2/BCLXLi) was the most effective in killing AML blasts of VEN-AZA refractory patients (mean IC50 70 nM) compared with venetoclax (BCL-2i) (1000 nM), A-1331852 (BCLXLi) (1000 nM) and S-63845 (MCL1i) (> 1000 nM)...Patients with high overall TNF expression (C1) were selectively responsive to the IAP inhibitors birinapant and LCL161 ex vivo, suggesting that inhibition of IAPs could be an effective approach for VEN-AZA resistant AML with increased TNF...Additionally, a MEP-like gene signature, combined with eleveted TNF expression in AML blasts, may contribute to venetoclax resistance while concurrently enhancing sensitivity to SMAC mimetics. These findings suggest potential therapeutic targets and stratification markers, paving the way for novel therapy approaches for VEN-AZA refractory AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • CD276 • CD34 • KIT • MCL1 • MECOM • PRAME • TP53

Phenotypic Drug Response Profiling Identifies Asparaginase-Based Synergistic Combinations for Very High Risk Acute Lymphoblastic Leukaemia (ASH 2023) - "Eight clinically relevant agents with promising sensitizing activity as identified by decreased area-under-the-curve with addition of ASNase were identified (SEL, selinexor; ELTA, eltanexor; VEN, venetoclax; BZM, bortezomib; navitoclax; carfilzomib; mitoxantrone, birinapant). We validated combinations of ASNase with the 8 selected drugs plus 4 drugs used in induction therapy (prednisolone, dexamethasone, vincristine and daunorubicin) using a 4x4 drug matrix in 15 high-risk ALL PDX samples...Our results identify XPO1 inhibitors as a new class of drugs with promising anti-leukaemic activity in BCP-ALL. Co-culture based DRP shows promise in identifying alternative novel sensitive synergistic combinations ex-vivo with decreased toxicity for patients who have an inadequate response to standard therapy."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • XPO1

Resistance to FLT3 Inhibitors in FLT3-Mutated AML Is Associated with CD45RA+CD200- leukemic Cells and Can be Overcome By Combination with SMAC Mimetics (ASH 2024) - "Subsequent validation confirmed synergy between the midostaurin and the SMAC-mimetics birinapant and LCL161, while the BH3 mimetic venetoclax and the PI3K inhibitor idelalisib only showed an additive effect. Our data shows specific differences in myeloid maturation and LSC (Leukemic Stem Cell) phenotype between midostaurin responders and non-responders, together with a potential functional shift in cell signaling in immune signaling and anti-apoptotic pathways. Moreover, ex vivo drug testing data demonstrates that while there is less overall sensitivity to drug treatment in non-responders, combination therapies including apoptotic modulators such as the SMAC mimetics could overcome FLT3i resistance and improve FLT3mut patient outcomes."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD200 • CD33 • CD40 • FLT3 • IL12RB1 • ITGAX • PD-L1

Radiation-induced senescence as a driver of glioblastoma recurrence (SNO 2025) - "Our findings illustrate how senescence of both stromal and tumor cells promote GBM recurrence via different mechanisms and underscore the potential utility of adjuvant senolytic therapy for blunting GBM recurrence. Ongoing studies are focused on combinatorial treatment with birinapant (to remove senescent GBM cells) and navitoclax (to remove senescent astrocytes) in order to prevent recurrence."

Brain Cancer • Glioblastoma • Glioma • Solid Tumor • BIRC3 • CDKN1A • IL6

Radiation-induced senescence as a driver of glioblastoma recurrence (SNO 2025) - "Our findings illustrate how senescence of both stromal and tumor cells promote GBM recurrence via different mechanisms and underscore the potential utility of adjuvant senolytic therapy for blunting GBM recurrence. Ongoing studies are focused on combinatorial treatment with birinapant (to remove senescent GBM cells) and navitoclax (to remove senescent astrocytes) in order to prevent recurrence."

Brain Cancer • Glioblastoma • Glioma • Solid Tumor • BIRC3 • CDKN1A • IL6

RB loss sensitizes triple-negative breast cancer to apoptosis induced by cellular stress. (PubMed, Cell Death Discov) - "Birinapant in combination with CHK1 or AURKA inhibitors results in selective cell killing in RB-deficient TNBC models and yields durable disease control via apoptosis in vivo. In conclusion, RB loss in TNBC displays an enhanced vulnerability to pro-apoptotic signaling that can enable the effective implementation of new targeted therapeutic strategies."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • RB1 • XIAP

Radiation-induced senescence as a driver of glioblastoma recurrence (WFNOS 2025) - "Our findings illustrate how senescence of both stromal and tumor cells promote GBM recurrence via different mechanisms and underscore the potential utility of adjuvant senolytic therapy for blunting GBM recurrence. Ongoing studies are focused on combinatorial treatment with birinapant (to remove senescent GBM cells) and navitoclax (to remove senescent astrocytes) in order to prevent recurrence."

Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • BIRC3 • CDKN1A • IL6

Radiation-induced senescence as a driver of glioblastoma recurrence (WFNOS 2025) - P1 | "Our findings illustrate how senescence of both stromal and tumor cells promote GBM recurrence via different mechanisms and underscore the potential utility of adjuvant senolytic therapy for blunting GBM recurrence. Ongoing studies are focused on combinatorial treatment with birinapant (to remove senescent GBM cells) and navitoclax (to remove senescent astrocytes) in order to prevent recurrence."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • BIRC3 • CDKN1A • IL6

Improving Anti-Tumor Efficacy of CAR T-Cell Therapy for Acute Myeloid Leukemia (AML): Results from a Multi-Drug Interaction Screening Approach (ASH 2023) - "Of all tested compounds birinapant, a peptidomimetic of second mitochondrial-derived activator of caspases (SMAC) and inhibitor of apoptosis protein (IAP) family proteins and the hypomethylating agent (HMA) decitabine showed the strongest improvement of CAR T cell cytotoxicity in an additive but also in a synergistic manner. Our data suggest that high throughput drug interaction screens are a reliable approach to investigate the impact of chemical compounds on the functionality of AML-specific CAR T-cell products. HMA and SMAC mimetics are promising candidates that may potentially enhance the cytotoxicity of CAR T-cells. Ongoing studies are evaluating the effect of HMAs and SMAC mimetics on CAR T-cell proliferation and anti-tumor efficacy against AML cell lines and primary AML patient samples upon serial antigen stimulation."

CAR T-Cell Therapy • Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD27 • CD33 • CD70

Revolutionizing B-ALL Cell Line Development: Novel Generation to Uncover Therapeutic Vulnerabilities (ASH 2024) - "LH lines showed resistance to many cytotoxic drugs, especially birinapant, inotuzumab, dexamethasone, and nelarabine...Additionally, we found LH samples also respond well to vincristine and JQ1, suggesting new vulnerabilities. Surprisingly, BCR : : ABL1+/BCR : : ABL1-like samples with IK6 were sensitive to dexamethasone and gilteritinib compared to those with wild type IKZF1, though complete cell eradication was not achieved even at high dosage, indicating combined therapy would be beneficial.In summary, we developed a new approach, generating 21 B-ALL cell lines spanning 11 subtypes. Combined with commercial lines, we now have seven LH lines, eight BCR : : ABL1-like lines, five HLF-r lines, and four near haploid lines to further study the mechanisms and therapeutic vulnerabilities of these high-risk B-ALL subtypes. These models provide an important resource for identifying dependencies and therapeutic vulnerabilities."

Preclinical • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • CRLF2 • IKZF1 • KMT2A • MEF2D • NTRK3 • NUTM1 • PAX5 • PBX1 • TCF3 • ZEB2

Enhancing Androgen Receptor Antagonist-Mediated Interferon Responses in Prostate Cancer (PCF 2025) - "By integrating RNA-seq and ChIP-seq (AR and H3K27Ac) data in VCaP cells, we found that AR binding sites are generally not associated with genes upregulated by AR inhibition using enzalutamide (Enz), suggesting indirect or epigenetically mediated repression...Treatment with the DNA methyltransferase inhibitor decitabine (DAC) upregulated ~55% of genes induced by Enz, while inhibition of H3K27 methylation via EZH2 inhibitor (GSK126) had a limited effect, underscoring the dominant role of DNA methylation in silencing EREs...Finally, co- treatment with Enz and birinapant, a SMAC mimetic that activates both canonical and non-canonical NF-κB signaling, produced a marked increase in HLA class I expression...• Prostate Cancer Foundation Young Investigator Award • Career Enhancement Program Awards (NIH/Dana-Farber/Harvard Cancer Center SPORE in Prostate Cancer) • BIDMC Philanthropy Pilot Award Conflicts of Interest Disclosure Statement. No conflicts of interest"

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ADAR • AR

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

USP13 depletion sensitizes colorectal cancer cells to necroptosis by destabilizing cIAP2 proteins. (PubMed, Cell Death Differ) - "The loss of USP13 significantly potentiates TNF-α/SMAC mimetic birinapant/pan-caspase inhibitor Z-VAD-FMK (TBZ)-induced necroptosis in CRC cells and diminishes tumor growth in a xenograft model. Thereby, USP13 may serve as a potential therapeutic target for anticancer treatment of CRC."

Journal • Colorectal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BIRC3 • TNFA • USP13

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: Mar 2026 ➔ Jul 2026

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

Opposing regulation of the K63-linked polyubiquitination of RIPK3 by SMURF1 and USP5 in necroptosis. (PubMed, Nat Commun) - "Reducing SMURF1, using a RIPK3 mutant defective in SMURF1-mediated ubiquitination, or overexpressing USP5 enhances necroptosis in leukaemia cells, leading to reduced tumour growth in xenograft models treated with birinapant and emricasan. These findings highlight the opposing regulation of K63-linked polyubiquitination of RIPK3 by SMURF1 and USP5 in necroptosis."

Journal • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • SMURF1 • USP5

Sequential Targeting of IAP and BCL-2 Family Proteins May Enhance Apoptotic Sensitivity in Non-Small Cell Lung Cancer (EACR 2025) - "Targeting survival pathways with Smac mimetics (e.g., Birinapant, Compound A) and BH3 mimetics (e.g., S63845, ABT-263) offers a promising approach...Necroptosis was assessed using RIPK1 and RIPK3 inhibitors (Necrostatin-1, GSK872) but did not significantly contribute to cell death.Group 2 cells underwent additional treatment with BH3 mimetics (S63845, ABT-199, WEHI-539, ABT-263)... Our findings highlight the importance of sequential drug administration in apoptosis induction. Smac mimetics effectively induced apoptosis in sensitive NSCLC cells, while resistant cells may require BH3 mimetics. The lack of necroptotic response confirms apoptosis as the primary mechanism."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ANXA5 • BCL2 • FHIT • KRAS • MCL1 • RIPK1 • TNFA • TP53

Multiscale Modeling Uncovers Macrophage Infiltration and TNF-α Signaling Networks for Targeting in Inflammatory Breast Cancer Tumor Emboli. (PubMed, bioRxiv) - "Our findings demonstrate enrichment of genes linked to chemotaxis and TNFR network of signals in the tumor cells and increased macrophage infiltration in the IBC tumor emboli microenvironment. Using a transgenic murine model, we demonstrate that treatment with Birinapant, a SMAC mimetic that enhances TNFα-mediated cell death, may be effective in targeting the tumor emboli phenotype."

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

Potential Inhibitors of SARS-CoV-2 Developed through Machine Learning, Molecular Docking, and MD Simulation. (PubMed, Med Chem) - "The results emphasize the efficacy of integrating molecular docking, machine learning, and molecular dynamics simulations in facilitating the rapid identification of novel inhibitors. PubChem ID: 23658468 demonstrates robust binding affinity to ACE2 and favorable pharmacokinetic properties, establishing it as a promising candidate for further investigation."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases