A-1331852 / AbbVie - LARVOL DELTA

Pseudo-Senescence Induced by Palbociclib Does Not Sensitize Pleural Mesothelioma Cells to Combinations With Classical Senolytics (IASLC-WCLC 2025) - "In mice models of MPM, abemaciclib and palbociclib reduced tumour growth and prolonged overall survival. Methods : We have studied the nature of senescence induced by the CDK4/6 inhibitor palbociclib and the chemotherapeutic drug cisplatin in commercial and patient-derived PM cell line models...We attempted to eradicate palbociclib pre-treated PM cells with conventional senolytics like Navitoclax and Dasatinib...Combining BH3 mimetics like venetoclax (Bcl-2 inhibitor), navitoclax, the specific Bcl-xL inhibitor A-1331852, or the Mcl-1 inhibitor S63845 with palbociclib did not enhance cell death...If palbociclib induces "pseudo-senescence" in mesothelioma, the clinical use of CDK4/6 inhibitors is challenged by the risk of tumour regrowth. Our findings underscore the complexity of therapy-induced senescence and the importance of understanding its nature when assessing the effectiveness of senolytics in specific tumour models."

IO biomarker • Breast Cancer • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • BCL2L1

BCL-xL dependency in chromophobe renal cell carcinoma. (PubMed, Cancer Gene Ther) - "We combined A-1331852 and S63845 with IKE or RSL3 (ferroptosis-inducing drugs). These data indicate that BCL-xL maintains ChRCC cell survival by suppressing apoptosis. The BCL-xL-specific PROTAC DT2216, currently in clinical trials, may provide an opportunity for ChRCC therapy."

Journal • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Targeted Protein Degradation • BCL2L1 • CASP3

Differential UVC radiation sensitivity in multidrug-resistant l1210 cells: Insights into p53 and Bcl-XL expression/function. (PubMed, J Photochem Photobiol B) - "Multidrug-resistant (MDR) variants of L1210 cells, selected for resistance to vincristine (R) or doxorubicin (D), exhibit elevated ABCB1 (P-glycoprotein) expression but differ in UVC sensitivity...Pharmacological inhibition of Bcl-XL in S and D cells with A-1155463 and A-1331852 enhanced UVC-induced cell death but did not replicate the high sensitivity observed in R cells. Our findings suggest that the heightened UVC sensitivity of R cells results from a combined deficiency of p53 and Bcl-XL, impairing DNA damage response and apoptosis. These results reveal distinct molecular adaptations in MDR variants and provide insight into the mechanisms underlying differential UVC sensitivity."

IO biomarker • Journal • ABCB1 • BCL2 • BCL2L1 • CDKN1A • TP53

Direct co-targeting of Bcl-xL and Mcl-1 exhibits synergistic effects in AR-V7-expressing CRPC models. (PubMed, Cancer Res Commun) - "Patients often develop resistance to next-generation 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) and a patient-derived organoid model (LuCaP 167 CR)...We showed similar synergistic efficacy with the Bcl-xL targeting PROTAC in combination with S63845 in the 3D spheroid models. Our findings support further preclinical development of Bcl-xL and Mcl-1 inhibitors for mCRPC."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • AR • BCL2L1 • CASP3 • CASP7

SORAFENIB REVERSES VENETOCLAX SECONDARY RESISTANCE IN ACUTE MYELOID LEUKAEMIA VIA DOWNREGULATION OF THE RAS-RAF-MEK-ERK SIGNALLING PATHWAY (EHA 2025) - "Peripheral leukemic cells were analysed via flow cytometry, haematological parameters were monitored through blood counts, and spleen size was measured post-treatment.High-throughput in vitro drug sensitivity screening identified six venetoclax-synergistic agents from thirty-one candidates: ruxolitinib, sorafenib, A1331852, mivebresib, quizartinib, and nilotinib. Sorafenib reverses secondary venetoclax resistance in AML by inhibiting the Ras-Raf-MEK-ERK pathway and downregulating anti-apoptotic proteins (BCL-2, MCL-1, BCL-XL), thereby synergising with venetoclax to inhibit resistant leukaemic cells. This study provides a promising therapeutic strategy for overcoming venetoclax resistance in AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • MCL1

IDENTIFYING SYNERGISTIC ACTIVITIES OF COMBINED INHIBITION OF TYROSINE KINASES AND ANTI-APOPTOTIC MOLECULES IN ABL1 FUSION-POSITIVE ALL (EHA 2025) - "Notably, dependencies of ABL1+ leukemias on BCL-2 family proteins changed significantly upon exposure to TKIs, thus suggesting an increased activity by combining inhibition of kinase activity and anti-apoptosis regulators.Therefore, we titrated combinations of the different TKIs (nilotinib, ponatinib or dasatinib) and BH3-mimetics (venetoclax, A-1331852 or S63845) in dose-response matrices analyzing the most effective combinations in ABL1+ cell lines by calculating efficacy and Bliss synergy scores. In conclusion, we found activities of different TKIs in ABL1+ ALL samples along with shifted dependencies on anti-apoptotic molecules. Importantly, combined inhibition of tyrosine kinases and anti-apoptotic molecules led to synergistic activities and increased cell death induction with the most effective combinations predicted by functional BH3-profiling. Thus, our findings form the basis for further (pre-) clinical evaluation of co-targeting tyrosine kinases and..."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCL2 • BCL2L1 • CRKL • MCL1

ASSESSING THE EFFICACY OF NK CELLS IN COMBINATION WITH BH3-MIMETICS IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (EHA 2025) - "To assess sensitivity of T-ALL for BH3-mimetics, we performed EC50 measurements for the BH3-mimetics venetoclax (BCL-2), A1331852 (BCL-XL), AZD4320 (BCL-2/BCL-XL) and AZD5991 (MCL-1). Taken together, we found heterogeneous sensitivity of T-ALL to NK cells and BH3-mimetics. These sensitivities were reflected in BH3-profiling assays, providing a potential marker of response. Combining NK cells with BH3-mimetics improved cell killing efficacy, suggesting further preclinical and potential clinical evaluation."

Clinical • Combination therapy • IO biomarker • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • Thrombocytopenia • BCL2 • BCL2L1 • IL15 • MCL1

Co-targeting of epigenetic regulators and BCL-XL improves efficacy of immune checkpoint blockade therapy in multiple solid tumors. (PubMed, Mol Cancer) - "Using flow cytometry and single-cell RNA sequencing of the tumor microenvironment, we found that the broad activity of the triple therapy relied on the expansion of T and NK cells with cytotoxic potential, an increase in the M1/M2 macrophage ratio, and a reduction of immunosuppressive Treg cells, dendritic cells, and B lymphocytes. In conclusion, we report a novel regimen combining epigenetic and BCL-XL inhibitors with ICB that produces potent anti-tumor responses in multiple preclinical models of solid tumors."

Checkpoint inhibition • IO biomarker • Journal • Brain Cancer • Breast Cancer • Colon Cancer • Colorectal Cancer • Glioblastoma • Hematological Disorders • Hematological Malignancies • Melanoma • Oncology • Solid Tumor • BCL2 • BCL2L1

Identification of novel therapies of Gastric Cancer (IGCC 2025) - "Gastric cancer BCL-XL dependence is a potential therapeutic target with selective inhibitors and synergise with FLOT chemotherapy agents."

IO biomarker • Gastric Cancer • Oncology • Solid Tumor • BCL2L1 • MCL1

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