LCL161 / Novartis - LARVOL DELTA

Final results of a phase 2 clinical trial of LCL161, an oral SMAC mimetic for patients with myelofibrosis. (PubMed, Blood Adv) - P2 | "SMAC mimetics may represent an option for older patients with thrombocytopenia or for those in whom prior JAK inhibitors has failed. This trial was registered at www.clinicaltrials.gov as #NCT02098161."

Clinical • Journal • P2 data • Fatigue • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Otorhinolaryngology • Pruritus • Thrombocytopenia • Vertigo • ASXL1 • TNFA

Inhalational therapy of pulmonary infection via macrophage-targeted nanoemulsions. (PubMed, Acta Pharm Sin B) - "Herein, we present a macrophage-targeted inhalable nanoemulsion for co-delivering rifampicin and LCL161, an inhibitor of apoptosis protein antagonist. Following two-dose inhalational administration, RL-NE@Man displayed potent bactericidal activity against M. tuberculosis while concurrently alleviating pulmonary pathological lesions and hyperinflammatory responses, demonstrating superior bacterial suppression efficacy compared with that of the first-line rifampicin monotherapy. This inhaled combination therapy, which integrates immunomodulators with antibiotics to modulate the local immune landscape and synergistically enhance bactericidal efficacy, represents a novel therapeutic strategy for precision tuberculosis management."

Journal • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • Tuberculosis

A novel mitochondrial-related signature to decode tumor immunity and predict survival in chromophobe renal cell carcinoma. (PubMed, Immunobiology) - "Notably, our computational analysis based on GDSC's pRRophetic algorithm suggests that LCL161 and UMI-77 may be more effective in the low-risk group, while sapitinib and luminespib show potential efficacy in the high-risk group. In conclusion, our study indicates this model holds high promise as a reliable biomarker for outcome prediction and precision-medicine stratification in chRCC patients."

Journal • Tumor mutational burden • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • RECQL4 • TERF1

Integration of single-cell and bulk transcriptomics reveals the association of manganese metabolism-related genes with prognosis and immune infiltration in lung adenocarcinoma. (PubMed, Clin Transl Immunology) - "Drug sensitivity analyses suggested that JQ1 and Vorinostat may be more effective in low-MRS patients, while Pevonedistat and LCL161 may be preferable for high-MRS patients. The synergistic antitumor effects of JQ1 and PTMA suppression were verified. This model provides a novel biomarker framework and therapeutic guidance for prognostic assessment and personalised treatment in LUAD."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Novel therapeutic strategies targeting MECOM rearranged AMLs discovered by unbiased drug screen (AACR 2025) - "Co-targeting with BETi and other identified sensitivities such as the IAP family inhibitor (LCL161) or Bcl-xL inhibitor (navitoclax or A1155463) also exhibited synergistic lethality in 3q26.2-r AML cell lines and PD AML cells. Co-treatment of mivebresib with dactolisib or LCL161 was superior than each drug alone in reducing AML burden and improving survival. These findings demonstrate promising preclinical activity of novel BETi-based combination with IAP or Bcl-xL inhibitor against AML with EVI1 overexpression."

Acute Myelogenous Leukemia • Oncology • BCL2L1 • GATA2 • MECOM • MYC • PIK3CA • TNFA • XIAP

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

Single-cell transcriptomic signatures identify drug combinations to address platinum resistance in ovarian cancer (ESGO 2026) - "Among 64 predicted drugs, the NEDD8-activiating enzyme (NAE) inhibitor pevonedistat, the inhibitor of apoptosis (IAP) inhibitor LCL161 and the bromodomain (BRD2/3/4) inhibitor birabresib, exhibited a long-term inhibitory effect in two organoid models. Even though this combination treatment did not result in significant survival benefit, it reduced the tumour size, metastatic dissemination and staging of the disease. Conclusion We demonstrate that targeting transcriptional resistance signatures with selective inhibitors can partially reverse carboplatin resistance in clinically relevant organoid and PDX models, supporting their potential as combination strategies to improve therapeutic response."

Oncology • Ovarian Cancer • Solid Tumor • BRD2

KIF5B-driven unfolded protein response reprograms breast cancer immunosuppressive microenvironment for single-cell guided therapeutic targeting. (PubMed, Discov Oncol) - "Our multimodal analysis establishes KIF5B as a prognostic biomarker and potential therapeutic target in BRCA, with implications for understanding immune evasion and guiding precision treatment strategies."

Journal • Breast Cancer • Oncology • Solid Tumor • BRCA • KIF5B

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

Discovery based on SPR drug chip that corilagin alleviates acute lung injury in mice by inhibiting necroptosis through targeting RIPK1/RIPK3/MLKL pathway. (PubMed, Chin J Nat Med) - "In vitro, corilagin inhibits necroptosis induced by either tuberculosis, tumor necrosis factor-α (TNF-α), LCL-161, and inhibitor (IDN-6556) (TSI) (tumor necrosis TNF-α combined with LCL-161 (a Smac mimic) and pan-caspase inhibitor IDN-6556), or lipopolysaccharide (LPS) with IDN-6556. In a mouse model of sepsis associated with necroptosis, corilagin administration reduces the severity of LPS-induced acute lung injury, correlating with decreased MLKL phosphorylation in lung tissues. These results indicate that corilagin attenuates RIPK1/RIPK3/MLKL signaling, potentially through reducing mtROS production, thereby inhibiting necroptosis and offering protection against LPS-induced acute lung injury."

Journal • Preclinical • Acute Lung Injury • Infectious Disease • Metabolic Disorders • Oncology • Pulmonary Disease • Respiratory Diseases • Septic Shock • Tuberculosis • RIPK1 • TNFA

BET inhibitor-based combinations targeting novel dependencies in MECOM-rearranged (r) AML. (PubMed, Leukemia) - "In a MECOM-r AML PDX model, mivebresib with dactolisib or LCL161, was superior to monotherapy or vehicle in reducing AML burden and increasing mouse survival. These findings highlight that cotreatment with BETi and PI3K/mTOR or IAP inhibitor exerts superior in vitro and in vivo efficacy in MECOM-r AML cells and support further evaluation of these BETi-based combinations."

Journal • Acute Myelogenous Leukemia • BCL2L1 • BRD4 • GATA2 • MECOM • MYC • PIK3CA • XIAP

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

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

Targeting Venetoclax Resistance in TP53-Mutated Acute Myeloid Leukemia (ASH 2023) - "Introduction: The combination therapy of Venetoclax (Ven) and Azacitidine (Aza) has shown remarkable improvements in the treatment of acute myeloid leukemia (AML) patients not eligible for chemotherapy...In contrast, the TP53-mutated blasts showed higher ex vivo sensitivity to Navitoclax (BCL-2/BCL-XL inhibitor) (Nav IC50=90nM, Ven IC50>1000nM). Additionally, LCL-161 (IAPs inhibitor) demonstrated notable efficacy in the TP53-mutants and was significantly more effective compared to the wild-type controls (LCL-161 IC50=300nM, Ven IC50>1000nM)... In the comparison of BCL-2 family protein expression and treatment responses, BCL-XL levels were significantly higher (p=0.03) in the treatment-resistant group, while no differences were found in BCL-2 or MCL-1 (Figure 1A). In the TP53-mutated blasts, a trend of decreased BCL-2 was identified compared to the TP53 wild-type blasts (p=0.08), but no difference in BCL-XL or MCL-1 levels was noted. However, all three..."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • CD34 • GATA1 • GATA2 • KIT • MCL1 • TP53

Efficacy of Combinations of Targeted Agents Against Dependencies in Mecom Rearranged AML Identified By Unbiased Chemical and CRISPR Screens (ASH 2024) - "Treatment of 3q26.2-r AML cell lines for 96-hours with ORY001 (LSD1i; 3-100 nM), RGFP966 (HDAC3i; 0.5-10 µM) or GNE-781 (CBP/p300i; 10-1000 nM) induced moderate, dose-dependent cell death, as determined by flow cytometry...Treatment of the luciferized 3q26.2-r PD AML242 model, engrafted in NSG mice, with mivebresib (0.5 mg/kg, daily 5x per week), dactolisib (20 mg/kg, daily 5x per week) or LCL161 (65 mg/kg, daily 5x per week) reduced AML burden and increased survival compared to vehicle-treated mice (p < 0.05)...These treatments resulted in reduction of EVI1 and c-Myc levels, associated with preclinical differentiation and apoptotic activity in the 3q26.2-r AML cell models. Further in vivo evaluation of the efficacy of BETi or LSD1i-based combinations against 3q26.2-r AML is warranted."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BRD4 • CD86 • GATA2 • HDAC3 • ITGAM • MECOM • MYC • PIK3CA • XIAP

SMAC mimetics induce human macrophages to phagocytose live cancer cells. (PubMed, Immunother Adv) - "Pharmacologic reprogramming with the SMAC mimetic LCL161 in combination with T-cell-derived cytokines can induce macrophages to phagocytose live cancer cells in mouse models...Unlike mouse macrophages, where a combination of SMAC mimetics with lymphotoxin enhanced phagocytosis, human macrophages were more efficiently polarized to phagocytose live cells by the combination of SMAC mimetics and IFNg. We profiled phagocytic macrophages by transcriptional and proteomic methodologies, uncovering a positive feedback loop of autocrine TNFa production."

Journal • Breast Cancer • Oncology • Pancreatic Cancer • Solid Tumor • IFNG • TNFA

Kaempferol enhances immunogenic cell death via premortem stress and necroptosis in cholangiocarcinoma: Insights from network pharmacology and mechanistic studies. (PubMed, Comput Biol Med) - "Kaempferol acts as a multi-target therapeutic agent in CCA by inducing ER stress, autophagy, and triggering necroptosis when combined with zVAD-FMK and LCL-161, while enhancing immunogenic cell death. These findings support its potential as a novel immunogenic cell death-based treatment strategy for CCA."

Journal • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • CALR • CAPN1 • CDC37 • HMGB1 • HSP90AA1 • HSPA8 • PPIA

Andrographolide prevents necroptosis by suppressing the generation of reactive oxygen species. (PubMed, Acta Biochim Biophys Sin (Shanghai)) - "Our results demonstrate that Andro notably inhibits necroptosis in the in vitro cellular models induced by either lipopolysaccharide (LPS) plus IDN-6556 or a combination of TNF-α, LCL-161 (Smac mimetic) and IDN-6556. In contrast, derivatives, including dehydroandrographolide, neoandrographolide, 14-deoxy-11,12-didehydroandrographolide, and 14-deoxyandrographolide, have no anti-necroptotic effects and fail to upregulate Nrf2. Collectively, our findings demonstrate that Andro specifically inhibits the RIPK1/RIPK3/MLKL signaling axis to suppress necroptosis, highlighting its therapeutic potential against necroptosis-related disorders."

Journal • Inflammation • BCL2 • RIPK1 • TNFA

Managing Myelofibrosis: Matching Advances in Treatments With Clinical Unmet Needs. (PubMed, Hematol Oncol) - "The janus kinase inhibitor (JAKi) ruxolitinib has been the mainstay of treatment for over a decade...Other JAKi (pacritinib, momelotinib, jaktinib) address treatment-related cytopenia, expanding the therapeutic utility of this class of agents to patients with baseline anemia or thrombocytopenia. Novel candidates exploit multiple molecular pathways, and offer the potential to improve the management of MF-associated cytopenia (imetelstat, pelabresib, navitoclax, selinexor, luspatercept, sotatercept, elritercept, LCL161, bomedemstat) and recover bone marrow fibrosis (imetelstat, pelabresib, navitoclax and bomedemstat). It remains to be seen if these newer agents can induce any remission in MF and enable patients to come off therapy, but the future is beginning to look much brighter."

Journal • Review • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Thrombocytopenia

CDK4/6 inhibitors upregulate cIAP1/2, and Smac mimetic LCL161 enhances their antitumor effects in cholangiocarcinoma cells. (PubMed, Sci Rep) - "However, we have demonstrated that CDK4/6 inhibitor palbociclib monotherapy is less effective in CCA cells. We further showed that this combination treatment has less effect on non-tumor cholangiocytes and human peripheral blood mononuclear cells (PBMCs). Our findings demonstrate for the first time that the combined treatment of Smac mimetics and CDK4/6 inhibitors is a promising novel targeted therapy for CCA patients."

Journal • Biliary Cancer • Cholangiocarcinoma • Hepatology • Oncology • Solid Tumor

cIAP2 supports the cell growth-promoting activity of FMR1 in gastric cancer via CARD-RING domains. (PubMed, Biochem Biophys Res Commun) - "The Smac Mimetic LCL161 reduced both FMR1 and cellular inhibitor of apoptosis protein 2 (cIAP2) levels...Collectively, our findings highlight FMR1's growth-promoting role in gastric cancer and reveal a novel function of cIAP2 in stabilizing FMR1 as an E3 ligase. These results suggest targeting cIAP2 could be an effective strategy for treating gastric cancer by downregulating both cIAP2 and FMR1."

Journal • Gastric Cancer • Oncology • Solid Tumor • BIRC3 • FMR1

SMAC mimetics induce human macrophages to phagocytose live cancer cells. (PubMed, bioRxiv) - "Pharmacologic reprogramming with the SMAC mimetic LCL161 in combination with T cell-derived cytokines can induce macrophages to phagocytose live cancer cells in mouse models...Unlike mouse macrophages where combination of SMAC mimetics with lymphotoxin enhanced phagocytosis, human macrophages were more efficiently polarized to phagocytose live cells by the combination of SMAC mimetics and IFNψ. We profiled phagocytic macrophages by transcriptional and proteomic methodologies, uncovering a positive feedback loop of autocrine TNFα production."

Journal • Breast Cancer • Oncology • Pancreatic Cancer • Solid Tumor • TNFA

Castrate-resistant prostate cancer response to taxane is determined by an HNF1-dependent apoptosis resistance circuit. (PubMed, Cell Rep Med) - "Monotherapy with cIAP2 inhibitor LCL161 is sufficient to treat HNF1A+ models of mCRPC previously resistant to docetaxel. These data may be useful in future clinical trial designs."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • BIRC3 • HNF1A