A-1331852 / AbbVie - LARVOL DELTA

Developing targeted therapy to induce apoptotic cell death post radiotherapy in glioblastoma (EANO 2026) - "Therefore, there is an urgent need to develop effective and targeted therapies to improve GBM outcomes in the future.Our group has recently demonstrated that targeting the anti-apoptotic protein BCLXL with the BH3 mimetic A1331852 in combination with radiotherapy (RT) increases tumour cell clearance both in vitro and in vivo... In this study we explore the efficacy of using lipid-based technology to specifically hit a previously validated therapeutic target, BCLXL, to induce GBM cell-targeted knockdown. We show that the design of delivery vehicles can be informed by the biology of GBM cells to increase uptake and present a promising approach for delivering therapeutics across the BBB to tumour cells while limiting toxicity."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • BCL2L1

Dual targeting of BCL-XL and MCL-1 exposes a rapid and exploitable apoptotic vulnerability in non-small cell lung cancer. (PubMed, Cell Death Differ) - "Consistent with previous reports, BH3 mimetics alone provided only limited and heterogeneous sensitization to cisplatin across NSCLC models...Accordingly, apoptosis was fully restored by next-generation BCL-XL inhibition (A-1331852) or by PROTAC-mediated BCL-XL degradation (DT2216). Importantly, platelet-sparing BCL-XL targeting strategies retained strong synergy with MCL-1 inhibition, addressing a key translational limitation of earlier BH3-mimetic approaches. Together, these data redefine apoptotic control in NSCLC as a cooperative restraint imposed by BCL-XL and MCL-1 rather than discrete, context-dependent dependencies, revealing a rapid, p53-independent mitochondrial apoptotic vulnerability with clear therapeutic implications."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BCL2 • BCL2L1 • TP53

Cell-type specific apoptotic patterns in pancreatic cancer stromal-tumor co-culture organoids (ESMO-GI 2026) - "This shows high expression of Bcl-Xl and Mcl-1 in PDOs and even higher expression after paclitaxel treatment indicating apoptotic priming...We showed significant decrease of cancer cells after treatment with Bcl-Xl inhibitor A-1331852...Conclusions We showed that PDOs and CAFs affect each other's apoptotic priming. Our findings offer novel insights into complex co-regulation of pro-survival functions in PC and may explain why BH3 inhibitors so far have met limited success."

IO biomarker • Stroma • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • BCL2 • BCL2L1 • CAFs • MCL1

Harnessing programmed cell death and metabolic vulnerabilities to enhance therapy in medulloblastoma (ISPNO 2026) - "In a panel of five MB cell lines, the BCL-XL inhibitor A1331852 or the MCL-1 inhibitor S63845 significantly enhanced tumour cell death when combined with cyclophosphamide or BAY-2402234. A CRISPR-Cas12 knockout screen in D425 MB cells identified potential resistance and sensitizer genes contributing to BAY-2402234 induced killing independent of BAK/BAX. Together, these findings support a novel combination treatment paradigm integrating BH3-mimetics with chemotherapy or metabolic inhibition, and highlight programmed cell death-based strategies as promising therapeutic avenues for medulloblastoma."

Brain Cancer • Medulloblastoma • Solid Tumor • BCL2 • BCL2L1 • CASP3

OT-55 reshapes tolerogenic BH3-mimetic-induced apoptosis toward immunogenic cell death in acute myeloid leukemia, potentiating PD-1/Tim-3 blockade. (PubMed, Cell Death Dis) - "While A-1331852 was cytotoxic yet weakly immunogenic, its combination with OT-55 enhanced DAMP release, increased CD8⁺ effector functions, and, with PD-1/Tim-3 blockade, achieved local and distant tumor control with low toxicity. These findings identify OT-55 as an immunogenic adjuvant converting tolerogenic BH3 mimetic-driven apoptosis into ICD, providing a proof-of-concept immunogenic treatment for myelomonocytic AML."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • ATG5 • BCL2L1 • CALR • CD8 • HAVCR2 • HMGB1 • IFNGR1 • IL1B • PDIA3 • PIK3CA • TLR4

Genotoxic antibody-drug conjugates combined with BCL-XL inhibitors enhance therapeutic efficacy in metastatic castration-resistant prostate cancer. (PubMed, J Clin Invest) - "Lastly, enhanced in vivo antitumor activity of vobramitamab duocarmazine by systemic A-1331852 was shown. Collectively, our findings provide rationale for the development of ADC therapies combining genotoxic payloads with BCL-XL inhibitors for mCRPC."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hematological Disorders • Oncology • Prostate Cancer • Solid Tumor • BCL2L1 • CD276 • STEAP1

Exploring the therapeutic potential of BclxL inhibitors with distinct modes of action in a living biobank of patient-derived ex vivo ovarian cancer models (OCMs) (ESMO-Gynae 2026) - "Methods We screened a panel of 20 OCMs representing diverse disease subtypes with the BclxL PROTAC DT-2216 and the BclxL-specific BH3 mimetic A-1331852. Comparable activity of the PROTAC and BH3 mimetic, together with the clinical advancement of DT-2216, supports further translational evaluation of BclxL degraders as a less toxic therapeutic strategy. Degradation efficiency alone did not predict DT-2216 response, highlighting the need to define additional determinants of PROTAC sensitivity and resistance."

Preclinical • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • BCL2 • BCL2L1

CLIP-TAC: A Novel Proteolysis-Targeting Degrader of BCL-XL in Multiple Myeloma (EACR 2026) - "Aims: To overcome thrombocytopenia, a proteolysis-targeting-chimera (PROTAC), called DT2216, was developed that couples navitoclax (BCLXL binder) to a von Hippel–Lindau (VHL) E3 ligase-recruiting ligand to selectively degrade BCLXL in tumour cells, while sparing platelets that lack VHL...Degradation was rescued by pre-treatment with A-1331852 (BCLXL inhibitor) or MLN-4924 (NEDD8-activating enzyme inhibitor), confirming on-target, proteasome-dependent activity...Co-targeting this compensation, either directly with MCL-1 inhibitor AMG-176 or indirectly with cyclin-dependent kinase inhibitors (CYC065, THZ1, Samuraciclib), synergistically enhanced DT2216-induced cell death... MM exhibits heterogeneous dependence on BCL-2 family proteins. BH3-profiling can identify BCLXL-reliant tumours. Targeted degradation of BCLXL with DT2216, or a novel Clip-TAC, shows therapeutic potential in MM."

Hematological Malignancies • Multiple Myeloma • Plasmacytoma • Targeted Protein Degradation • Thrombocytopenia • Von Hippel-Lindau Syndrome • BCL2 • BCL2L1

INFLUENCE OF NON-BCR::ABL1 SOMATIC MUTATIONS ON TYROSINE KINASE INHIBITOR (TKI) RESISTANCE IN CHRONIC MYELOID LEUKEMIA (EHA 2026) - "Combination drug screening (imatinib or asciminib plus additional compounds) identified a synergistic effect between asciminib and the BCL-XL inhibitor A-1331852 specifically in BCOR-KO cells. Moreover, BCOR-mutated CML exhibited a distinct sensitivity profile to combination treatment with asciminib and BCL-XL inhibitor. Schematic of CROP-seq experimental work-flow"

Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • ABL1 • APAF1 • ASXL1 • BCL2L1 • BCOR • DNMT3A • IKZF1 • MED23 • RUNX1 • TET2 • TP53

NOXA/MCL-1 axis determines cell-death decision between apoptosis and a GSDME-dependent cell death associated with production of inflammatory cytokines upon treatment of breast cancer cells with antimitotics. (PubMed, Cell Death Dis) - "Indeed, genetic inactivation of NOXA, which reinforces the pro-survival function of MCL-1 in cancer cells, only postpones death upon exposure to Taxol and BCL-xL antagonism with A1331852. Importantly, a comparative analysis of secretomes from NOXA-proficient and NOXA-deficient cancer cells treated with Taxol revealed variations in the production of inflammatory cytokines, including IL-1α, IL-1β, and IL-18. Thus, induction of apoptosis or a vacuole-associated and inflammatory cell death, in breast cancer cells by antimitotic treatment, relies on pore-forming protein GSDME expression but also on a fine balance within the BCL2 family network."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • BCL2 • BCL2L1 • CASP3 • GSDME • IL18 • IL1B • MCL1

Pseudo-senescence induced by palbociclib does not sensitise pleural mesothelioma cells to combinations with senolytics. (PubMed, Cell Death Dis) - "The CDK4/6 inhibitors abemaciclib and palbociclib have demonstrated promising results in patient-derived xenograft models of PM...While some cells showed sensitivity to Bcl-xL inhibitors, neither navitoclax nor the specific Bcl-xL inhibitor A-1331852, nor other BH3 mimetics targeting Bcl-2 (venetoclax) or Mcl-1 (S63845) increased cell death when combined with palbociclib...Therefore, we employed inhibitors of these pathways, such as dasatinib, momelotinib or Torin-1, which did not synergise with palbociclib to kill the cells...The differential effects of palbociclib and cisplatin on permanent growth arrest were verified by sorting PM cells based on size and β-galactosidase activity. Our findings underscore the importance of understanding the nature of therapy-induced senescence when assessing the effectiveness of senolytics in different tumour models."

Journal • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • BCL2 • BCL2L1 • CXCL8 • IL6

Beyond apoptosis: Novel biological mechanisms of BCL-xL inhibition in Merkel cell carcinoma (SID 2026) - "In vivo, treatment with navitoclax or the selective BCL-xL inhibitor A-1331852 significantly slowed tumor growth in MCC xenograft models. Collectively, these findings support BCL-xL inhibition as a compelling therapeutic strategy in MCC. The antitumor activity and mechanistic effects observed in preclinical models support further translational development and clinical evaluation of therapies targeting BCL-xL, particularly for patients who do not benefit from immunotherapy."

Genetic Disorders • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • BCL2 • BCL2L1

PRMT5 inhibition alters cellular chromatin landscape and drives vulnerability to BH3 mimetics in mantle cell lymphoma (AACR 2026) - "Drug combination effects of PRT382 and BH3-mimetics (navitoclax, A852/A-1331852, PRT1419) were tested in MCL cell lines (n=5). Our study showed the broad synergistic potential of combining PRMT5i and BH3 mimetics both in vitro and in vivo. PRMT5i lead to epigenome-wide modulation of chromatin states with potential to create vulnerabilities to targeted agents."

IO biomarker • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2

Assessing cancer drug combination efficacy across 900+ PRISM cell lines in a multiplexed screening assay (AACR 2024) - "In the first combination, temozolomide+O6-benzylguanine (alkylating agent + MGMT inhibitor), we found that cell lines expressing MGMT were sensitized to temozolomide in the presence of O6-benzylguanine, thus illustrating synergy. In the second combination, we screened two anti-apoptosis compounds A-1331852+AZD5991 (BCL-xL + MCL1 inhibitor) and found that BCL-xL and MCL1 inhibition were also synergistic. In the third combination, ML210+ferrostatin-1 (GPX4 inhibitor inducing ferroptosis + ferroptosis inhibitor), we found that ferrostatin-1 antagonized the effects of ML210. Our analysis also reveals the importance of appropriate dose selection and analytical metrics for reliably measuring combined effects. In conclusion, the PRISM platform's multiplexed cell line screening is a robust method for characterizing rationally designed drug combinations, offering a systematic approach to enhance the precision of combination therapy development in cancer care."

Preclinical • Oncology • BCL2L1 • GPX4 • MGMT

Therapeutic potential of BH3-mimetics and NK cell-mediated immunotherapy in T-ALL. (PubMed, Cell Death Dis) - "Here, we analyzed the sensitivity of T-ALL to inhibitors of BCL-2 (venetoclax), BCL-XL (A1331852), MCL-1 (AZD5991) and dual inhibition of BCL-2/BCL-XL (AZD4320) and evaluated their combination effects with natural killer (NK) cells. Importantly, NK cell-mediated killing could be further enhanced by combining NK cells with AZD4320, proposing this combination as a potential effective treatment. Taken together, we demonstrated promising potential of BH3-mimetics and NK cells for the treatment of T-ALL alone and in combination, warranting further preclinical and potential clinical evaluation."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • BCL2L1

Organoid models of ovarian clear cell carcinoma for evaluating therapeutic sensitivity (AACR 2025) - "The OCCC PDO was treated with standard-of-care chemotherapies carboplatin and paclitaxel; BCL-XL inhibitor A1331852 (Selleckchem); a novel BCL-XL PROTAC degrader DT2216 (Dialectic Therapeutics); or combinations of the BCL-XL inhibitor/degrader with paclitaxel. These data suggest that BCL-XL inhibition/degradation combined with paclitaxel may be a promising treatment strategy for OCCC. Our study also demonstrates the successful establishment of OCCC PDOs and application of a microfluidic device for evaluating novel therapeutic strategies in ovarian cancer."

Clear Cell Carcinoma • Oncology • Ovarian Cancer • Solid Tumor • ARID1A • BCL2L1 • CASP3 • CASP7 • CDKN2A • CDKN2B • HER-2 • PIK3CA

Direct co-targeting of Bcl-xL and Mcl-1 exhibits synergistic anti-cancer effects in AR-V7-expressing mCRPC preclinical models (AACR 2025) - "Patients often develop resistance to hormonal therapies that target the AR-axis (e.g., abiraterone, enzalutamide)...Combinations targeting Bcl-xL (A-1331852 and Navitoclax) and Mcl-1 (S63845) synergistically decreased cell viability and induced apoptotic activity via cleavage of PARP, caspase 3, and caspase 7 across AR-V7 expressing CRPC cell lines (LNCaP95, VCaP-CR, 22Rv1) as early as two hours post-treatment...Our findings provide unique insight into the dependence on Bcl-2 family proteins in mCRPC. Our findings also support further preclinical development of Bcl-xL and Mcl-1 inhibitors for mCRPC."

Preclinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • BCL2 • BCL2L1 • CASP3 • CASP7

Investigation of BH-3 mimetics as radiosensitizing agents in glioblastoma (AACR 2024) - "Treatment consists of maximal safe tumor resection, chemotherapy (temozolomide) and radiotherapy; however, this aggressive treatment offers only a modest improvement in outcomes, with average life expectancy of approximately 12 months. Overall, we have demonstrated that dependence on BCL-2 family proteins is a vulnerability that can be targeted to improve radiotherapy response in GBM. Furthermore, we have identified a promising BH3 mimetic, A1331852, to use in combination with RT and have completed a proof-of-concept in vivo study that confirms the potential of BH3 mimetics to improve outcomes for patients with GBM."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • BCL2 • BCL2L1 • MCL1

Mitochondrial bioenergetics-SASP crosstalk determines senolytic efficacy in therapy-induced senescence. (PubMed, Cell Death Discov) - "Inflachromene, an inhibitor of the chromatin remodelers HMGB1/2, decoupled mitochondrial bioenergetics from senolytic susceptibility, yielding SASP-null/miR146a-negative senescent cancer cells that were completely resistant to ABT-263/navitoclax and A1331852 despite extensive mitochondrial reprogramming. Thus, the senolytic response is governed by a layered circuit in which mitochondrial bioenergetic heritage establishes the senolytic ceiling, TIS-acquired bioenergetic flexibility fine-tunes the amplitude of the senolytic response, and establishing a mitochondria-inflammatory SASP crosstalk is required for BH3-mediated senolysis. These results support using functional readouts that integrate mitochondrial metabolic flexibility and inflammatory SASP to predict and potentially enhance senolytic efficacy in TIS cancer cells."

Journal • Oncology • BCL2L1 • HMGB1 • MIR146A

FRET-SAM: SAM_Med2D-based automatic FRET two-hybrid analysis. (PubMed, Comput Methods Programs Biomed) - "By enabling automated analysis of FRET images, FRET-SAM significantly enhances the efficiency and accuracy of FRET two-hybrid assays, while eliminating subjective bias. The capability of FRET-SAM to resolve drug-target interactions establishes it as a promising tool for drug discovery."

Journal • Hepatocellular Cancer • Lung Cancer • Oncology • Solid Tumor • BCL2L1 • EGFR

Targeting Bcl-xL to eliminate chemotherapy-induced tumor dormancy and prevent breast cancer metastasis. (PubMed, Br J Cancer) - "Dormancy was induced with low-dose FAC (5-Fluorouracil, Adriamycin, Cyclophosphamide). Notably, disseminated cell frequency inversely correlated with primary tumor size during neoadjuvant chemotherapy, underscoring the need for systemic therapies targeting distant dormant cells. These findings identify Bcl-xL as a central survival factor in chemotherapy-induced dormancy, and suggest that tumor-targeted systemic delivery of A-1331852 may eradicate disseminated dormant cells and prevent metastatic relapse in high-risk TNBC."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BCL2L1 • BIRC5 • HER-2

Inhibition of PRMT5 with JNJ-64619178 sensitizes B-cell non-Hodgkin lymphoma cells to both intrinsic and extrinsic apoptosis (ASH 2025) - P1 | "Various cell lines, including DLBCL (TMD8, Ri-1, OCI-Ly1,OCI-Ly1R, SUDHL4), double-hit lymphoma patient-derived xenograft (DW19), MCL (Mino, Jeko-1), and BL(Raji, BL-70) were utilized to investigate the in vitro anti-cancer properties of JNJ-9178, BH3 mimetics(venetoclax [Ven, BCL-2i], S63845 [S63, MCL-1i], A1331852 [A133, BCL-xLi]) and TRAIL analogs (rhTRAIL[recombinant human TRAIL], Conatumumab [DR5 agonist], and Mapatumumab [DR4 agonist]). We identified PRMT5 as an important regulator of both intrinsic and extrinsic apoptosis. Ourdata suggest that DBP has the potential to optimize the selection of BH3 mimetics to combine with JNJ-9178 to maximize the activity of this drug across certain B-cell NHL subtypes. Additionally, JNJ-9178sensitizes B-cell NHL cell lines to TRAIL-induced cancer cell-selective extrinsic apoptosis."

IO biomarker • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Solid Tumor • ANXA5 • BCL2 • TNFRSF10B

SRSF2 mutation induces BH3 mimetics sensitivity via BCL2L2 mis-splicing (ASH 2025) - "Interestingly, SRSF2 mutation conferred increased sensitivity tothe MCL1 inhibitor (S-63845) or the BCL2L1 inhibitor (A-1331852) in AML cell lines that were otherwiseinsensitive to venetoclax, in a manner dependent on their intrinsic BH3 family protein expression profile.These findings suggest that SRSF2 mutations induce a shift in apoptotic dependency, with variableconsequences shaped by the intrinsic anti-apoptotic landscape of the cell.To uncover the molecular basis of this shift, we analyzed the expression of BCL2 family members inSRSF2-mutant and wild-type cells. Our results uncover amechanistically defined and therapeutically actionable vulnerability in SRSF2-mutant AML and providebroader insight into how splicing factor mutations reshape apoptotic regulation in leukemia. Thesefindings may inform the rational design of combination therapies and support the development ofprecision medicine strategies targeting splicing-derived vulnerabilities in AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • BCL2L1 • BCL2L2 • GLI2 • SRSF2

Synergy between enzalutamide and selective Bcl-2 family inhibitors in metastatic castration-resistant prostate cancer (ESMO Asia 2025) - "While venetoclax (Bcl-2 inhibitor) combinations with enzalutamide have entered clinical evaluation, the relative benefit of inhibiting different Bcl-2 family members under identical experimental conditions has not been directly compared. DU145 mCRPC cells were treated for 48 h with enzalutamide (ENZA) alone or in combination with ABT-199 (Bcl-2 inhibitor), A-1331852 (Bcl-xL inhibitor), or AZD5991 (Mcl-1 inhibitor). In a direct comparison under uniform conditions, Mcl-1 inhibition with AZD5991 emerged as the most effective partner for ENZA in DU145 cells, followed by Bcl-xL inhibition, while Bcl-2 inhibition was less impactful. These findings support further evaluation of Mcl-1-targeting strategies as a means to overcome AR-independent resistance in mCRPC, while underscoring the need for cautious interpretation of large in-vitro dose-reduction estimates."

IO biomarker • Metastases • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ANXA5 • BCL2L1

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