S63845 / Servier, Novartis, HitGen - LARVOL DELTA

Slow-Cycling and Cycling Persister Cells in Multiple Myeloma Share Adaptive Apoptotic Priming as a Common Resistance Mechanism (IMS 2026) - " To investigate persister emergence, we utilized the doxycycline (dox ) inducible Histone-2B-mCherry (H2B-mCherry) from the watermelon library to measure cell proliferation...KMS-11 cells were treated with lenalidomide (LEN), MCL1 inhibitor S63845 (S63), the DNA alkylating agent melphalan (MPN) and proteasome inhibitor bortezomib (BTZ) . OCI-MY5 cells were treated with the BCL2 inhibitor venetoclax (VEN), MPN, S63 and BTZ... T ogether, t hese data demonstrate that drug - tolerant persister cells exist and are phenotypically heterogeneous in MM . It remains to be determined if these pers ister cells are an acquired state or are pre -exis ting within tumors ."

Hematological Malignancies • Multiple Myeloma • BCL2L1

Targeting MCL-1 Overcomes Adaptive Resistance to PI3K Inhibition in Thymic Carcinoma (IASLC-WCLC 2026) - "Pharmacologic MCL-1 inhibition with S63845 further enhanced the antitumor effect of buparlisib, resulting in greater growth suppression and increased apoptosis compared with either monotherapy alone. Dual targeting of PI3K and MCL-1 restored apoptotic sensitivity and produced synergistic antitumor effects in human TC models. These findings support combined PI3K and MCL-1 inhibition as a promising therapeutic strategy for overcoming treatment resistance in a subset of patients with TC."

Mantle Cell Lymphoma • Oncology • Solid Tumor • Thymic Carcinoma • Thymus Cancer

A clinically translatable next-generation EVA strategy for glioblastoma: combining eltanexor and BH3-mimetics drives synergistic apoptosis. (EANO 2026) - "Background:Glioblastoma (GB) is characterized by marked aggressiveness, poor clinical outcome, and rapid development of resistance to currently available treatments. Replacing the original Venetoclax/A1210477 backbone with Navitoclax and a clinically advanced MCL-1 inhibitor resulted in substantially enhanced anti-glioblastoma activity and robust synergistic effects, with MIK665 showing superior performance compared with S63845 across experiments. These data support further development of Navitoclax and MIK665 as core components of a next-generation EVA strategy with strong translational potential."

Clinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • BCL2 • BCL2L1 • BCL2L2 • CASP3

SLC22A4 alleviates early brain injury after subarachnoid hemorrhage with partial involvement of MCL1. (PubMed, Brain Res Bull) - "In OxyHb-treated astrocytes, SLC22A4 overexpression increased MCL1 expression and attenuated apoptosis- and oxidative stress-related responses, whereas pharmacological inhibition of MCL1 with S63845 partially reversed these protective effects. Collectively, these findings suggest that SLC22A4 alleviates EBI after SAH, partly through MCL1-associated suppression of apoptosis and oxidative stress."

Journal • CNS Disorders • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Subarachnoid Hemorrhage • Vascular Neurology • MCL1 • SLC22A3

Effects of BCL-2 and MCL-1 Inhibition on Apoptotic and Transcriptional Profiles in Acute Myeloid Leukemia. (PubMed, Medicina (Kaunas)) - "We studied the effects of the BCL-2 inhibitor ABT-737, the MCL-1 inhibitor S63845, and their combination on AML cell lines and primary AML patient cells. BCL-2 and MCL-1 inhibition, alone or in combination, induced apoptosis and altered the expression of epigenetic regulators and oncogenes in AML cell lines and primary patient cells, with no consistent advantage of combined treatment over single agents. BCL-2/MCL-1 inhibition remains a promising approach for AML, and further work should clarify which patients or disease subtypes are most likely to benefit from combined versus single-agent treatment."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • CASP9 • DNMT1 • HDAC1 • SUZ12 • WT1

Repurposing BH3 mimetics to deplete tumour-infiltrating regulatory T cells and enhance anti-tumour immunity in non-small cell lung cancer. (PubMed, Cell Death Differ) - "Pharmacological inhibition of MCL-1 with the BH3 mimetic S63845 induced moderate apoptotic cell death in both human and murine tumour-infiltrating Tregs, coincident with transient enhancement of CD8⁺ T cell activity...Mechanistically, we found that IL-33 upregulated MCL-1 expression and was required to support activated tumour-infiltrating Tregs. These results establish MCL-1 as an important regulator for tumour-infiltrating Treg survival and highlight the potential of repurposing BH3 mimetics to modulate immune suppression in NSCLC."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BCL2 • CD8 • FOXP3 • IL33

Therapeutic development of the clinically active compound ACT001 with Mcl-1 inhibitors for the treatment of paediatric diffuse midline glioma (ISPNO 2026) - P1 | "Mcl-1 inhibitors (MIK665 and AZD5991) showed the strongest synergy consistent with ACT001-mediated suppression of anti-apoptotic signalling...In vivo, ACT001, the Mcl-1 inhibitor S63845, and their combination each extended survival without evidence of synergy in orthotopic DMG models and reduced Ki67-positive tumour cells...Collectively, these findings indicate that ACT001 is a multi-targeted agent that disrupts NF-κB and apoptotic signalling while promoting oxidative stress and the unfolded protein response. Combining ACT001 with inhibitors of anti-apoptotic proteins represents a promising therapeutic strategy for patients with DMG."

Clinical • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • Pediatrics • Solid Tumor • NQO1 • RELA

BCL-xL is required throughout human megakaryocyte differentiation to restrain intrinsic apoptosis and sustain platelet production (ISTH 2026) - "We used two pharmacological inhibitors of BCL-xL (ABT-263 and WEHI-539) and one selective Mcl-1 inhibitor S63845. Our results reveal major differences between human and murine megakaryopoiesis and have important clinical implications for the development of BCL-xL–targeting anticancer therapies, as impaired platelet production may contribute to treatment-associated thrombocytopenia. DOI*10.1016/j.rpth.2026.105118"

IO biomarker • Thrombocytopenia • BCL2 • BCL2L1 • CD34

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

Inhibition of MCL-1-mediated anti-apoptotic signalling as a potential therapeutic strategy for paediatric high-grade gliomas (ISPNO 2026) - P1/2 | "Selective MCL-1 inhibitors (S63845, MIK665, BRD-810) and the BCL-2 inhibitor venetoclax were screened in cytotoxicity assays, with MIK665 showing the greatest efficacy against both HGG and DMG cells. The discovery that MCL-1 inhibition restores H3K27me3 reveals a novel mechanistic link between apoptotic evasion and epigenetic dysregulation. The robust synergy with epigenetic inhibitor CBL-0137 provides a compelling rationale for further preclinical development in DMG and HGG tumours."

IO biomarker • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • High Grade Glioma • Mantle Cell Lymphoma • Pediatrics • Solid Tumor • ANXA5 • PDGFRA

VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes (EACR 2026) - "Thus, we describe mitochondrial molecular fingerprint that discriminates liver from hepatocarcinoma and allows sparing normal tissue while targeting tumors."

Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • BCL2 • VDAC2

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

Targeting BCL2 pathway to enhance immunogenicity in ALK+ NSCLC (AACR 2026) - "However, this has not been studied in the context of ALK+ NSCLC.We hypothesized that ALK-directed therapy in combination with BH3 mimetics would initiate ICD through the release of DAMPs and increase sensitivity to ALK TKIs. We evaluated the efficacy of ALK TKIs (Lorlatinib, Alectinib) alone and in combination with the BH3 mimetics navitoclax (BCL-2/BCL-xL inhibitor), venetoclax (BCL-2 inhibitor) and s63845 (MCL-1 inhibitor) to induce damage-associated molecular patterns (DAMPs) in ALK+ NSCLC cell lines. ALK+ cancer cell lines exhibited high expression of MCL-1 and BCL-xL proteins, indicating their dependency on BCL-2 family proteins for survival. ALK-directed therapy has the potential to induce immunogenic cell death (ICD) and elicit antitumor immune responses. Combining BH3 mimetics with ALK TKIs can be a promising therapeutic strategy to enhance anti-tumor immunity and overcome ALK TKI resistance in ALK+ NSCLC"

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BCL2L1 • CXCL10 • IFNB1

The mitochondrial antioxidant mitoquinone alters cancer cell death outcomes in response to therapy (AACR 2026) - "Therefore, to investigate how cell death outcomes might be adapted by changes to the cellular redox environment we used the mitochondrial antioxidant Mitoquinone (MitoQ) as a tool compound to dissect differences between apoptosis and ferroptosis outcomes in response to chemotherapeutic agents. Wild-type and BAX-/-BAK-/- HeLa (human cervical cancer) cells, as well as B16-F10 (metastatic murine melanoma) wild-type cells were treated with MitoQ (0.1-1 µM) alone or in combination with either an apoptosis-inducing cocktail of BH3 mimetics (1 µM ABT-263 + 1 µM S63845) or a ferroptosis-inducing cocktail (1 µM RSL3 + 1 µM Erastin2). These findings suggest that modulation of mitochondrial oxidative stress via MitoQ modulates cancer cell death outcomes, promoting apoptosis while suppressing ferroptosis at low doses. Further work is needed to elucidate the molecular mechanisms underlying these effects and their implications for modulating cancer cell death..."

Cervical Cancer • Melanoma • Oncology • Solid Tumor • ANXA5 • CASP3 • CASP7 • GPX4

The Bcl-xL specific PROTAC, DT2216, increases the sensitivity to target therapy of preclinical tumor models from different origin (AACR 2026) - "Moreover, when used in combinational regimen, we proved that DT2216 potentiated the efficacy of: a BRAF inhibitor (Dabrafenib) and a MEK inhibitor (Trametinib) in BRAFV600E/K melanoma cell lines; Trametinib in BRAF wild type melanoma cell lines; Dabrafenib in BRAFV600E/K colorectal cancer cell lines; a KRAS inhibitor (MRTX1133) in KRASG12D pancreatic cancer cell lines; a PARP-1 inhibitor (Olaparib) in breast and ovarian cancer cell lines...In melanoma models, DT2216 also induced a potentiating effect on ABT-199, a Bcl-2 specific inhibitor, and S63845, a Mcl-1 specific inhibitor. Finally, we validated our in vitro results by using xenograft mouse melanoma model in which DT2216 potentiated the effect of target therapy, showing a significant reduction of tumor growth and conferring a longer disease control. In conclusion, our results highlighted the relevance of targeting the Bcl-xL protein as a potential therapeutic strategy in combinatorial regimens with target therapies..."

Late-breaking abstract • Preclinical • Colorectal Cancer • Melanoma • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • BCL2 • BCL2L1 • KRAS

Profiling protein-protein interactions to predict sensitivity to drugs targeting BCL2 family members in lymphoma models (AACR 2025) - "Drug sensitivity parameters were integrated with protein data using Spearman Correlation and Multiple Linear Regression (MLR, Lasso). We exposed MCL (n=10, JVM2, REC1, JEKO1, UPN1, SP49, SP53, MAVER1, GRANTA519, Z138, MINO), MZL (n=6, VL51, SSK41, Karpas1718, HC1, HAIRM, ESKOL) cell lines and MZL models of secondary resistance (MZL-RES) to idelalisib (n=2), copanlisib (n=2), ibrutinib (n=2), venetoclax (n=1) and copanlisib/venetoclax (n=2), to BCL2i (venetoclax, sonrotoclax), BCL2/BCXLi (navitoclax), and MCL1i (S63845). Anti-apoptotic inhibitors show variable heterogeneous activity in MCL and MZL models, including those resistant to PI3Ki and BTKi, which could be predicted quantifying the BCL2-family members levels and interactions using the SPID. Such an approach might have a clinical potential to predict the sensitivity of patients with mature B cell lymphomas to this class of agents."

IO biomarker • Acute Myelogenous Leukemia • B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL2L1

KS18, an Mcl-1 inhibitor, triggers cell death and enhances the therapeutic efficacy of venetoclax in bortezomib-resistant multiple myeloma cells (AACR 2024) - "KS18 outperforms other Mcl-1 inhibitors such as S63845, VU661013, and AZD5991, according to the findings of our research, which shows that it is extraordinarily effective against MM cells that have become resistant to bortezomib. These intriguing findings highlight the potential value of KS18 as an adjunct to therapies aimed at overcoming bortezomib resistance in MM and other associated cancers. Bortezomib-resistant malignancies provide a challenge for patients, but additional research into the clinical value of KS18 holds the potential to improve treatment outcomes and broaden the range of therapeutic alternatives available to these patients."

Clinical • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • BCL2

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

Effect of MCL-1 inhibitor on organoids derived from cholangiocarcinoma patients with IDH1 mutation (AACR 2024) - "Patients with inoperable cholangiocarcinomas typically undergo chemotherapy regimens, including Gemcitabine, but their efficacy is limited, leading to low 5-year survival rates...Indeed, exposure to S63845, an MCL-1 inhibitor, significantly inhibited cell proliferation in IDH1-mutated cholangiocarcinoma organoids, unlike in IDH1 wild-type cholangiocarcinoma organoids. Furthermore, the combination of MCL-1 inhibitor and BCL-XL inhibitor demonstrated a synergistic and potent growth inhibitory effect on cholangiocarcinoma organoids. These findings indicate that the MCL-1 inhibitor holds promise as a new therapeutic agent for cholangiocarcinoma patients with IDH1 mutations."

Clinical • Acute Myelogenous Leukemia • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • CNS Tumor • Gastrointestinal Cancer • Glioma • Hematological Malignancies • Leukemia • Mantle Cell Lymphoma • Oncology • Solid Tumor • BCL2L1 • IDH1

Targeting MCL1 or SOS1 can overcome lenvatinib resistance in HCC (AACR 2025) - "Vetting these leads using a multidose titration assay showed synergy with LEN across all three LR models for two drugs: MRTX0902 targeting SOS1, an intracellular RTK signaling protein, and S63845 targeting MCL1, an anti-apoptosis protein. We also showed that targeting these components (SOS1 and MCL1) synergizes with LEN and inhibits cancer growth. These findings may become relevant patient treatments to extend patient survival against liver cancer."

Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • ANXA5

Dynamic switching of apoptosis-modulating BIM heterodimers in response to BH3 mimetics in xenograft models of hematologic malignancies. (PubMed, Mol Cancer Ther) - P1 | "Our results elucidate quantitative pharmacodynamics of S63845, venetoclax, and cirtuvivint, an agent that is currently being evaluated with venetoclax to treat AML (NCT06484062). Compensatory increases in off-target Bim heterodimer levels in response to either S63845 or venetoclax offer a possible mechanism of clinical drug resistance."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Oncology • BCL2 • BCL2L1 • CASP3 • MCL1

SMARCA4/2 loss reduces BCL-xL expression and confers a druggable MCL1 dependency in cancer. (PubMed, NPJ Precis Oncol) - "Furthermore, single-agent treatment of S63845 resulted in significant suppression of tumor growth in patient-derived xenografts of SMARCA4/2-deficient NSCLC and SCCOHT. Collectively, our work uncovered MCL1 as a synthetic lethal target in SMARCA4/2-deficient cancers that may be exploited therapeutically."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • BCL2 • BCL2L1 • MCL1 • SMARCA2 • SMARCA4

Synthetic lethality of MCL-1 inhibition and CAR-T therapy in aggressive B-cell lymphoma. (PubMed, Leukemia) - "In this study, we report the presence of residual drug-tolerant persister (DTP) and resistant lymphoma cells remaining within a highly immunogenic tumor microenvironment (TME) induced by the MCL-1 inhibitor (MCL-1i) S63845...Together, these findings highlight a synergistic, dual-pronged therapeutic strategy targeting both tumor-intrinsic survival pathways and the immunosuppressive TME. This combinatorial one-two-punch approach offers a promising path to eliminate DTP and residual disease, prevent relapse and pave the way for deep clinical remissions in aggressive B-cell lymphomas."

IO biomarker • Journal • B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • MYC • STAT1

Targeting MCL-1 and MAPK overcomes venetoclax resistance in FLT3-ITD-positive AML cells harbouring activating PTPN11 (SHP-2) mutations. (PubMed, Br J Haematol) - "Cells were treated with VEN, the MCL-1 inhibitor S63845 and the mitogen-activated protein kinase (MEK) inhibitor trametinib (TRA), alone or in combination. The presented results highlight the role of MAPK-driven MCL-1 and BCL(x)L expression, which mediates VEN resistance. While dual inhibition of B-cell lymphoma 2 and MCL-1 is already effective, additional MEK inhibition may further improve outcomes in PTPN11-mutated AML."

Journal • Acute Myelogenous Leukemia • B Cell Lymphoma • Leukemia • Lymphoma • Oncology • BCL2 • BCL2L1 • FLT3 • PTPN11

PROTAC-mediated degradation of Bcl-xL potentiates target therapy in preclinical melanoma models. (PubMed, J Exp Clin Cancer Res) - "Our findings provide new insights for combination therapy including Bcl-xL degradation for melanoma treatment."

Journal • Preclinical • Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • BCL2L1 • BRAF • CASP7