A-1331852 / AbbVie - LARVOL DELTA

Evaluation of the efficacy of novel ADCs as potential therapy options for colorectal cancer using a patient derived organoid model (DGHO 2025) - "This study investigates novel ADCs targeting B7-H3 (mirzotamab clezutoclax, ABBV-155) and EGFR (ABBV-637) linked to a Bcl-xL inhibitor as payload as therapeutic strategies for colorectal cancer using a PDO system. Four selected PDOs from CRC patients were maintained in long-term culture...Additionally, an internalization assay utilizing a pH-sensitive fluorescent dye (pHAb) was performed to assess drug uptake and intracellular localization of the ADCs. Untargeted inhibition of Bcl-xL with small molecule inhibitor A-1331852 caused significant cell viability loss (max reduction: 97% at 10 µM) and organoid structural disintegration, with efficacy correlating with baseline protein expression (r = 0.92)...Combinatorial targeting (ABBV-155 + Mcl-1 inhibitor ABBV-467) synergistically enhanced cell death (viability reduction: 62.6% vs. 0% monotherapy). These data provide critical insights into the use of novel ADCs as therapeutic options for CRC patients and suggest that..."

Clinical • Colorectal Cancer • Oncology • Solid Tumor • BCL2L1 • EGFR

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

MNT: a new target for AML. (PubMed, Blood Neoplasia) - "Mnt deletion provoked the apoptosis of MLL::AF9 AML cells in vitro and increased apoptosis elicited by the BH3 (BCL-2 homology region 3) mimetic drugs S63845 (MCL-1 (Myeloid cell leukemia-1) specific), ABT-199/Venetoclax (BCL-2 (B-cell lymphoma-2) specific), and A-1331852 (BCL-XL (B-cell lymphoma-extra large) specific). Of note, inducing MNT deletion in a human MLL-rearranged AML cell line transplanted into NSG (NOD SCID Gamma) mice debulked established leukemia and significantly extended the survival of transplant recipients. Taken together with previous studies that demonstrated a critical role for MNT in the development and sustained expansion of B and T lymphomas, our results suggest that a small molecule inhibiting MNT function may be a valuable therapeutic agent for myeloid and lymphoid malignancies."

IO biomarker • Journal • Acute Myelogenous Leukemia • B Cell Lymphoma • Leukemia • Lymphoma • Oncology • Transplantation • BCL2 • BCL2L1 • MCL1 • MYC

Anchored in Resistance: Overcoming Nidogen-2 (NID2) - mediated Immunoresistance in Ovarian Cancer with Ras and Bcl-xl Inhibition (AACR-NCI-EORTC 2025) - "This discrepancy highlights an urgent need to uncover tumor-intrinsic resistance mechanisms that may impair ACT efficacy in OC. To investigate mechanisms of immunotherapy (IT) resistance in OC, we developed OVCAR3-derived cell models resistant to Ipilimumab/Nivolumab in vivo (OV3IE) and to BiTEDs in vitro (OV3R), and established patient-derived organoids (PDOs) from IT responders and non-responders...Pharmacologic inhibition of either pathway - using the pan-Ras inhibitor ADT-007 or Bcl-xl inhibitors (Navitoclax, Venetoclax, A-1331852) - restored cytotoxicity in NID2-high models, including resistant PDOs. NID2 is a tumor-intrinsic driver of IT resistance in OC, acting through Ras activation and Bcl-xl upregulation. NID2 is a tumor-intrinsic driver of IT resistance in OC, acting through Ras activation and Bcl-xl upregulation. It may serve as a predictive biomarker for ACT response. Targeting this pathway, particularly via Bcl-xl inhibitors offers a mechanistically..."

IO biomarker • Oncology • Ovarian Cancer • Solid Tumor • BCL2L1 • MUC16 • NID2

Inhibition of Bcl-xL empowers the antineoplastic activity of TTFields in malignant Glioma in vitro (EANO 2025) - "In addition, flow cytometric analyses revealed that a simultaneous treatment with the Bcl-xL inhibitor A-1331852 and TTFields significantly increased the fraction of annexin V-positive (apoptotic) glioma cells... These data suggest that Bcl-xL inhibition enhances the susceptibility of malignant glioma cells towards TTFields. This effect seems to be, at least in part, due to a caspase-dependent cell death mechanism. Further studies are warranted."

IO biomarker • Preclinical • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor • ANXA5 • BCL2 • BCL2L1 • CASP3 • MCL1

Combined treatment with photodynamic therapy and Bcl-xL inhibition has a predominantly synergistic antineoplastic activity in medulloblastoma in vitro (EANO 2025) - "In this study, we performed a preclinical testing of a combined treatment with 5-ALA-based photodynamic therapy (PDT) and the Bcl-xL inhibitor A-1331852 in vitro.Material and The combination therapy was tested on established, primary cultured and stem-like medulloblastoma cells using MTT assays... PDT in combination with Bcl-xL inhibition had a predominantly synergistic inhibitory effect on the cell viability of a broad panel of medulloblastoma cells. This effect was associated with enhanced cleavage of caspases and energy depletion. Further studies are warranted."

Preclinical • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • ANXA5 • BCL2L1 • CASP9 • MYC

Investigating novel radiotherapy-BH3 mimetic combinations in glioblastoma (EANO 2025) - "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 radiotherapy and have completed a proof-of-concept in vivo study that confirms the potential of BH3 mimetics to improve outcomes for patients with GBM."

IO biomarker • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • BCL2 • BCL2L1 • MCL1

The BH3-only protein NOXA is essential for apoptosis induction by BH3-mimetics targeting BCL2 or BCL-XL in DLBCL. (PubMed, Br J Haematol) - "Here, we investigated the underlying mechanisms of inherent resistance to the BCL2i ABT-199 and BCL-XL inhibitor A1331852, focusing on the roles of the principal pro-apoptotic BH3-only proteins NOXA and BIM. Resistance to BCL2i and BCL-XL inhibitors was abrogated by suppression of MCL1 expression. In conclusion, we show that NOXA is essential for the effectiveness of BH3-mimetics targeting BCL2/BCL-XL; in the absence of NOXA, BIM displaced from BCL2/BCL-XL can be bound by MCL1."

IO biomarker • Journal • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL2L1 • PMAIP1

ARL3 Enhances ERα Stability via USP10 Deubiquitination to Promote Endocrine Resistance and Drive Mitochondrial Metabolic Reprogramming in HR+ Breast Cancer. (PubMed, Adv Sci (Weinh)) - "In preclinical models, the small-molecule inhibitor A-1331852 (targeting ARL3) potently suppresses ERα-positive tumor growth and synergizes with endocrine therapies. These findings establish ARL3 as a critical regulator of ERα homeostasis via USP10, highlighting its dual role as a biomarker and ARL3-targeted therapeutic for ERα-positive breast cancer."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • Targeted Protein Degradation • ER

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

Predictors of response and rational combinations for the novel MCL-1 inhibitor MIK665 in acute myeloid leukemia. (PubMed, Mol Oncol) - "To induce sensitivity, we treated MIK665-resistant samples with ABCB1 inhibitors elacridar or tariquidar, BCL-XL inhibitor A1331852, or BCL-2 inhibitor venetoclax in combination with MIK665. Additionally, the combination of MIK665 with venetoclax restored sensitivity in samples with primary venetoclax resistance. Overall, this study indicates that elevated ABCB1 expression is a potentially targetable resistance mechanism in the context of MIK665 resistance, and that a combination of MIK665 with venetoclax may be effective for overcoming resistance to either MCL-1 or BCL-2 inhibition."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ABCB1 • BCL2L1

Genotoxic antibody-drug conjugates combined with Bcl-xL inhibitors enhance therapeutic efficacy in metastatic castration-resistant prostate cancer. (PubMed, bioRxiv) - "Lastly, we found enhanced in vivo antitumor activity in mCRPC by combining the clinically relevant agents B7-H3-seco-DUBA (vobramitamab duocarmazine) and A-1331852. Collectively, our findings provide rationale for the development of ADC therapies combining genotoxic payloads with Bcl-xL inhibitors for mCRPC. B7-H3, PSMA, and STEAP1 targeted ADC therapies combining genotoxic payloads with Bcl-xL inhibitors induce p53-dependant apoptotic cell death in mCRPC, providing a clinically viable strategy for the treatment of advanced prostate cancer."

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

Ex vivo Evaluation of BCL-2 Family Member Dependencies in Multiple Myeloma: Synergistic Combinations and Biomarkers of Sensitivity and Resistance (IMS 2025) - "Ex vivo data were integrated with molecular (WES, RNA-Seq) and clinical data using Fisher's Exact Test (mutations), enrichment analysis (transcriptional data), and adapted univariate Cox models to identify features associated with increased synergy or sensitivity ex vivo. ABBV-467, an MCL-1 inhibitor, was the most potent single agent, with LD50 values in the nanomolar range...The BCL-2 inhibitor venetoclax was highly effective in MM with t(11; 14), gain18q, trisomy 13, mutations in ARID2, XBP1, CYLD and HUWE1, "CD1" and "CD2" subtypes, and those overexpressing BCL2. In contrast, BCL-XL inhibition with A-1331852 showed limited single-agent activity...Interestingly, MCL-1 inhibition + Pom demonstrated increased activity in t(14; 16) samples, and consistent with preclinical data, BCL-2 inhibition synergized with panobinostat... BCL-2 and MCL-1 are the dominant anti-apoptotic BCL-2 family effectors in MM. While MCL-1 inhibition may effectively target..."

IO biomarker • Preclinical • Hematological Malignancies • Multiple Myeloma • ARID2 • BAK1 • BCL2 • BCL2L1 • CD2 • HUWE1 • PTPN11 • XBP1

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

Development and Validation of a Scaffold-Free Human Multilineage Spheroid Model for Early Stage Cholangiopathies Driven by Cholangiocyte Senescence. (PubMed, Liver Int) - "This 3D multilineage spheroid model offers a mechanistically relevant and scalable platform to study cholangiocyte senescence-driven fibrosis. Its applicability to senolytic drug testing supports its use in preclinical screening and translational research across a spectrum of cholangiopathies."

Journal • Fibrosis • Hepatology • Immunology • Infectious Disease • Liver Cirrhosis • Novel Coronavirus Disease • Primary Biliary Cholangitis • BCL2L1

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