A-1331852 / AbbVie - LARVOL DELTA

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

Automated FRET Two-Hybrid Analysis. (PubMed, J Biophotonics) - "Applied to Bcl-xL/Bak interactions under A1331852 treatment, LURS revealed dose-dependent stoichiometry reduction ( ). The method achieved precise signal extraction while preserving native cellular conditions, overcoming throughput constraints in dynamic protein interaction studies."

Journal • BCL2L1

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

Discovery of XZ338, a highly potent BCL-XL degrader. (PubMed, Eur J Med Chem) - "In this study, XZ338, a highly potent and selective BCL-XL degrader derived from BCL-XL specific inhibitor A-1331852, was generated. XZ338 is 70-fold more potent than ABT-263 against MOLT-4 T-ALL cells, with over 89-fold selectivity for MOLT-4 cells over human platelets."

Journal • Hematological Disorders • Neutropenia • Oncology • T Acute Lymphoblastic Leukemia • Targeted Protein Degradation • Thrombocytopenia • BCL2L1

Mitochondrial priming and response to BH3 mimetics in "one-two punch" senogenic-senolytic strategies. (PubMed, Cell Death Discov) - "Replicative, mitotic, oxidative, and genotoxic forms of TIS were induced in p16-null/p53-proficient, BAX-deficient, and BRCA1-mutant cancer cells using mechanistically distinct TIS-inducing cancer therapeutics, including palbociclib, alisertib, doxorubicin, bleomycin, and olaparib...Furthermore, regardless of senescence-inducing therapeutic, stable/transient senescence acquisition, or genetic context, all TIS phenotypes shared a variable but significant senolytic response to the BCL-xL-selective BH3 mimetic A1331852. These findings may help to rethink the traditional assumption of the primed apoptotic landscape of TIS cancer cells. BCL-xL is a conserved anti-apoptotic effector of the TIS BCL2/BH3 interactome that can be exploited to maximize the efficacy of "one-two punch" senogenic-senolytic strategies."

BRCA Companion diagnostic • IO biomarker • IO Companion diagnostic • Journal • PARP Companion diagnostic • Oncology • BAX • BCL2 • BCL2L1 • BRCA1

Inhibition of Cyclin-Dependent Kinase 9 Rapidly Induces Apoptosis in Acute Lymphoblastic Leukemia and Shows Synergistic Activity with BH3-Mimetics (ASH 2024) - "Using the multi-CDK inhibitor dinaciclib, which targets CDK1, 2, 5 and 9, and the specific CDK9 inhibitor AZD4573, we analyzed the effects of both inhibitors in a series of ALL cell lines (BCP-ALL n=10, T-ALL n=6) and primary, patient-derived xenograft (PDX) samples (BCP-ALL n=15, T-ALL n=9)...Based on this, we investigated combinatorial inhibition of CDK9 (AZD4573) together with inhibitors of BCL-2 or BCL-XL (venetoclax, A-1331852, AZD4320) using dose-response matrix analyses and found enhanced cell death and synergistic activity for both combinations...However, intrinsic insensitivity due to dysbalanced protein levels of pro-survival proteins might limit efficacy. Combining CDK9 inhibition with inhibitors of the anti-apoptotic molecules BCL-2/BCL-XL significantly enhances cell death, thus overcoming insensitivity and providing an effective, novel therapeutic anti-ALL strategy to be further evaluated for clinical application."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • ANXA5 • BCL2L1 • CASP3 • CDK1 • CDK9 • MCL1

Bcl‑xL‑specific BH3 mimetic A‑1331852 suppresses proliferation of fluorouracil‑resistant colorectal cancer cells by inducing apoptosis. (PubMed, Oncol Rep) - "Furthermore, A‑1331852 suppressed the growth of xenograft tumors derived from 5‑FU‑resistant cells by inducing apoptosis. Overall, the present findings suggested that Bcl‑xL upregulation contributes to 5‑FU resistance of colorectal cancer and targeted inhibition by A‑1331852 may be an effective treatment strategy."

Journal • Colorectal Cancer • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • BCL2 • BCL2L1 • MCL1

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

Mechanistic Insights and Therapeutic Potential of a PRMT5 Inhibitor Combined with Venetoclax in B Cell Malignancies (ASH 2024) - P1, P1/2 | "DLBCL (TMD8, RI-1, OCI-Ly1, SUDHL4), double-hit lymphoma (DHL) patient-derived xenograft (PDX) cell line (DW19), MCL (Mino, Jeko-1), and Burkitt lymphoma (Raji) cell lines were utilized to investigate the in vitro anti-cancer properties of P1 and BH3 mimetics (venetoclax [BCL2i], S63845 [S63, MCL-1i], A1331852 [A133, BCL-xLi], Selleckchem). The caspase 8 inhibitor Z-IETD-FMK also rescued drug-induced cell death, but not as much as Z-VAD-FMK, suggesting potential activation of the extrinsic apoptosis pathway by the combined use of P1 and venetoclax. Conclusions : Our study suggests that the combination of a PRMT5 inhibitor P1 with venetoclax potently induces both intrinsic and extrinsic apoptotic cell death and may serve as a potential therapeutic strategy to explore further for DLBCL and MCL."

IO biomarker • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • ANXA5 • CASP8

Protein Degrader WH25244 Eliminates Venetoclax Resistance Factors: Mutant or Hyperphosphorylated BCL2, and BCL-XL (ASH 2024) - "WH25244 is a bifunctional molecule derived from navitoclax that recruits VHL E3 ligases to BCL2 and BCL-XL proteins, resulting in degradation via the ubiquitin-proteasome system...As assessed by CellTiter-Glo at 24h, WH25244 was potent against four cell lines sensitive to the BCL-XL inhibitor A-1331852 (EC50s 5000 nM) : MOLT-4 (EC50 = 4 nM), PF-382 (EC50 = 20 nM), SUP-T11 (EC50 = 30 nM), and CCRF-CEM (EC50 = 350 nM)...In conclusion, our results indicate that WH25244 can degrade mutant BCL2, hyperphosphorylated BCL2, and BCL-XL, overcoming multiple mechanisms that drive resistance to venetoclax. These data justify continued preclinical and future clinical investigation of WH25244 in CLL."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • ANXA5 • BCL2 • BCL2L1 • MCL1 • NCAM1

HRK downregulation and augmented BCL-xL binding to BAK confer apoptotic protection to therapy-induced senescent melanoma cells. (PubMed, Cell Death Differ) - "When analyzing potential therapeutic strategies, we observed a stronger senolytic activity in these melanoma cell lines when specifically targeting BCL-xL using A-1331852, navitoclax or the PROTAC BCL-xL degrader DT2216. Furthermore, we identified that the main apoptotic inhibition was shaped by BCL-xL and BAK binding increase that prevented mitochondrial permeabilization and apoptosis. To our knowledge, this is the first time that the molecular basis for BCL-xL anti-apoptotic adaptation in senescence is described, paving the way for the development of new molecules that either prevent HRK downregulation or displace BCL-xL binding to BAK to be used as senolytics."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • BCL2 • BCL2L1 • BCL2L2

Targeting Advanced Prostate Cancer with Antibody-Drug Conjugate (ADC) Combinations (PCF 2024) - "(2) Genotoxic payloads (duocarmycin, doxorubicin, camptothecin analogs, pyrrolobenzodiazepines, calicheamcycin), as well as ADCs bearing genotoxic payloads, synergize with the Bcl-xl inhibitor A-1331852. This work addresses challenges associated with ADC monotherapy in mCRPC and explores the potential of rational ADC combinations. We nominate B7-H3 and STEAP1 as targets for dual ADC therapy, and we propose to use DNA-damaging agents and Bcl-xl inhibitor A-1331852 as payloads for B7-H3 and STEAP1-targeting ADCs. Synergistic interactions between genotoxic ADCs and ADCs bearing A-1331852 have the potential to elicit effective tumor killing in mCRPC."

Metastases • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • BCL2L1 • STEAP1

SIGNIFICANCE OF HETEROGENEOUS BILIARY EPITHELIAL SENESCENCE AS A POSSIBLE TARGET OF NEW THERAPIES IN PRIMARY BILIARY CHOLANGITIS (AASLD 2024) - "Background: New therapeutic strategies are demanded for the patients with primary biliary cholangitis (PBC) showing inadequate response for ursodeoxycholic acid (UDCA) therapy...Cultured biliary epithelial cells (BECs) were treated etoposide, serum depletion or glycochenodeoxycholic acid (GCDC) for 4-7 days, then examined for cellular senescence, proliferative activity, apoptotis, mRNA and protein expression of various SASPs, p62 and PD-L1. The effect of senolytic drugs such as Dasatinib and A-1331852 was also determined in senescent BECs... There is a distinct heterogeneity in biliary epithelial senescence in PBC. Senolytic drugs and PD-1 inhibitors targeting PD-L1-positive senescent BECs may be promising new therapies for PBC patients with inadequate UDCA responses."

Heterogeneity • IO biomarker • Hepatology • Immunology • Primary Biliary Cholangitis • CCL2 • CDKN1A • CDKN2A

Enfortumab Vedotin Induces a Drug-Tolerant Persistent Urothelial Cancer Cell State Which Can Be Targeted via BCL-XL Inhibition (DGU 2024) - "Introduction: Enfortumab Vedotin (EV), an anti-NECTIN-4 Antibody-Drug-Conjugate (ADC) delivering a spindle toxin, has been approved for patients with metastatic urothelial carcinoma. Our data highlight the novel therapeutic concept of combining EV and BCL-XL inhibition for patients with UC."

IO biomarker • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • BCL2 • BCL2L1 • MCL1

Different modes of Bcl-xL inhibition, different outcomes? (EACR 2024) - "As a result, inhibition of Bcl-xL is synergistic with chemotherapy agents that delay progression through mitosis, e.g. paclitaxel. Western blotting of cell lines sensitive to A-1331852 but not DT-2216 confirmed the expression of von Hippel-Lindau protein, which is required for PROTAC function.Conclusion Ovarian cancer cell lines display a spectrum of sensitivity to Bcl-xL inhibitor treatment. Our ongoing research will investigate the molecular factors behind sensitivity and resistance to these inhibitors, initially focussing on Mcl-1 inhibition in A-1331852 resistant cell lines and assessing VHL function in DT-2216 resistant cell lines, leading to the identification of potential biomarkers for validation in the clinic."

Oncology • Ovarian Cancer • Solid Tumor • Targeted Protein Degradation • Von Hippel-Lindau Syndrome • BCL2L1

Improved drug target deconvolution with PISA-DIA using an extended, overlapping temperature gradient. (PubMed, Proteomics) - "Importantly, we demonstrate our PISA-DIA approach has the quantitative and statistical rigor using A-1331852, a specific inhibitor of BCL-xL. Due to the high melt temperature of this protein target, we utilized our extended multiple gradient PISA-DIA workflow to identify BCL-xL. We assert our novel overlapping gradient PISA-DIA-MS approach is ideal for unbiased drug target deconvolution, spanning a large temperature range whilst minimizing target dropout between gradients, increasing the likelihood of resolving the protein targets of novel compounds."

Journal • BCL2L1

Evaluation of BH3 mimetics as a combination therapy with irradiation in head and neck squamous cell carcinoma. (PubMed, Biomed Pharmacother) - "Our findings encourage the further preclinical investigation of BH3 mimetics, particularly A-1331852, as a single agent or combined with irradiation as a treatment for HNSCC."

Combination therapy • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • BCL2 • CAFs

Profiling of BCLxL Protein Complexes in Non-Small Cell Lung Cancer Cells via Multiplexed Single-Molecule Pull-Down and Co-Immunoprecipitation. (PubMed, Anal Chem) - "Notably, the NSCLC cell line EBC-1 exhibited high BCLxL-BAX and BCLxL-BAK levels, which closely paralleled a strong response to the BCLxL inhibitor A-1331852. This streamlined method offers the potential for quantitative biomarkers derived from protein complex profiling, paving the way for their application in protein complex-targeted therapies."

Journal • Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • BCL2L1

Co-operation of MCL-1 and BCL-XL anti-apoptotic proteins in stromal protection of MM cells from carfilzomib mediated cytotoxicity. (PubMed, Front Oncol) - "Pro-survival proteins: MCL-1, BCL-2 and BCL-XL were inhibited using S63845, ABT-199 and A-1331852 respectively. Furthermore, MCL-1 inhibition led to enhanced binding between BCL-XL and BIM, while blocking BCL-XL increased MCL-1/BIM complex formation, indicating the cooperative role of these proteins. Stromal interactions alter the dependence on BCL-2 family members, providing a rationale for dual inhibition to abrogate the protective effect of stroma and restore sensitivity to CFZ."

IO biomarker • Journal • Stroma • Hematological Malignancies • Multiple Myeloma • Oncology • BCL2 • BCL2L1 • MCL1

Molecular targeting of Bcl-xL during chemotherapy-induced tumor dormancy can inhibit breast cancer relapse (IMMUNOLOGY 2024) - "To target such survival pathway in FVBN202 transgenic mouse model of neu-overexpressing breast cancer, we first established tumor dormancy by means of a low dose immunogenic chemotherapy (FAC, 5-FU + Adriamycin + Cyclophosphamide) of the neu-overexpressing mouse mammary carcinoma (MMC) while using a specific inhibitor of Bcl-xL, A-1331852...In addition, selective knockdown of Bcl-xL in MMC by means of shRNA prevented relapse of chemotherapy-induced dormant tumor cells. Our findings suggest tumor-targeted delivery of A-1331852 during chemotherapeutic treatment of early-stage breast cancer for the prevention of distant recurrences of the disease."

Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BCL2L1 • ER

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

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

Uncovering metabolic and apoptotic vulnerabilities in multiple myeloma (EACR-AACR 2024) - "Apoptotic vulnerabilities were determined by sensitivity to BH3 mimetics (BCL2 inhibitor: venetoclax; MCL1: AMG176 and BCLXL: A1331852) by annexin v/propidium iodide staining...JJN3 and KMS27 showed a reliance on OXPHOS metabolism, while KMS12BM were the least dependent on OXPHOS. Next, the sensitivity of MM cells to a complex I inhibitor (IACS010759) was investigated...Conclusion Next, we aim to uncover the mechanism of the increased reliance on BCLXL. Through these innovative assays, we hope to uncover the metabolic and apoptotic vulnerabilities in MM patient samples, to potentially identify personalised therapies for enhanced survival."

Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • ANXA5 • BCL2L1

Development of novel 3D models for pediatric cancer (DKK 2024) - "Treatment of primary spheroids with BH3-mimetics indicates sensitivity to the BCLXL-inhibitors A1331852 and ABT-263 (Navitoclax) as well as to attack by activated allogenic NK cells. By using primary cell cultures we are currently developing novel tools for pre-clinical assessment of novel drugs or immunotherapies."

Clinical • CNS Tumor • Neuroblastoma • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • BCL2L1

The function of the BH3-only protein NOXA for BH3-mimetic-induced apoptosis in lymphoma cells (DKK 2024) - "Lab-based studies indicate that specific inhibitors of MCL-1 (S63845) and BCL-XL (A1331852) might also be effective in DLBCL, outlining alternative treatment strategies... Loss of NOXA significantly reduced sensitivity to ABT-199 or A1331852, highlighting its importance for apoptosis induced by BH3- mimetics targeting BCL-2 or BCL-XL... The findings can help to use this kind of therapeutics in a more targeted way for the therapy of lymphoma patients in the future."

IO biomarker • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • BCL2 • BCL2L1 • PMAIP1