S63845 / Servier, Novartis, HitGen - LARVOL DELTA

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

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

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

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

Ultrasound-Driven Coassembly of Anticancer Drugs into Carrier-Free Particles. (PubMed, ACS Nano) - "Venetoclax (Vtx) (as a model anticancer drug) is combined with an anticancer anthracycline drug, doxorubicin (Dox), or a myeloid cell leukemia-1 inhibitor drug (S63845) to form spherical, submicrometer-sized (∼200-1000 nm in diameter) particles, consisting predominantly of the drug molecules stabilized by hydrophobic interactions. Microscopy analysis of tumor tissues confirmed greater tissue damage and apoptosis induced by the NDs than those induced by the free drugs. The present findings highlight the potential of sono-driven assembled carrier-free systems in anticancer combination therapy, combining the advantages of a high surface area and slow-release particulate system with the synergistic action of multiple drugs to combat drug resistance."

Journal • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • MCL1

Both direct and indirect suppression of MCL1 synergizes with BCLXL inhibition in preclinical models of gastric cancer. (PubMed, Cell Death Dis) - "While the effect of S63845 is mediated by both BAX and BAK in most cases, BAX, rather than BAK, acts as the primary mediator of BCLXLi in GC cells...Mechanistically, anti-mitotic chemotherapies induce MCL1 degradation via the ubiquitin-proteasome pathway mainly through FBXW7, whereas HER2-targeting drugs suppress MCL1 transcription via the STAT3/SRF axis. The combination of the STAT3 inhibitor and BCLXL inhibitor also exhibits synergistic killing, extending beyond HER2-amplified GC."

IO biomarker • Journal • Preclinical • Cardiovascular • Gastric Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BCL2 • BCL2L1 • FBXW7 • HER-2 • MCL1

VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes. (PubMed, Nat Commun) - "Furthermore, in vivo, combination of S63845, a selective Mcl-1 inhibitor, with tumor-nectrosis factor-related, apoptosis-induncing ligand (TRAIL) peptide reduces tumor growth, but only in tumors expressing VDAC2. Thus, we describe mitochondrial molecular fingerprint that discriminates liver from hepatocarcinoma and allows sparing normal tissue while targeting tumors."

Journal • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • BCL2

Src inhibition potentiates MCL-1 antagonist activity in acute myeloid leukemia. (PubMed, Signal Transduct Target Ther) - "The importance of MCL-1 in leukemogenesis has prompted development of MCL-1 antagonists e.g., S63845, MIK665. These findings argue that Src inhibitors such as SKI-606 potentiate MCL-1 antagonist anti-leukemic activity in vitro and in vivo by blocking MCL-1 antagonist-mediated cytoprotective MCL-1 accumulation by promoting degradative ubiquitination, disrupting STAT-3-mediated transcription, and inducing NOXA-mediated MCL-1 degradation. They also suggest that this strategy may improve MCL-1 antagonist efficacy in AML and potentially other malignancies."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • BCL2L1 • CD34 • MYC

Combination Interaction Effects of Ibrutinib with Variety Drugs in in Vitro Mesenchymal Stromal Cell System in Chronic Lymphocytic Leukemia (ASH 2024) - "Annexin-V/PI apoptotic cell death assays were employed to evaluate the effects of TME-directed drugs including everolimus (mTOR inhibitor), MI-2 (MALT1 inhibitor), ruxolitinib (JAK1/2 inhibitor), S63845 (MCL-1 inhibitor), and venetoclax (Bcl-2 inhibitor) either as single agent, or in combination with ibrutinib on CLL B cells in direct contact with MSCs. The observed difference in effectiveness between high and low-risk cohorts when treated with ibrutinib plus MI-2 or ruxolitinib suggests these combinations would be beneficial for a subset of patients with high risk CLL. These preclinical data offer preliminary insights that support the evaluation of therapeutic combinations in patient with high-risk CLL : a population with significant unmet medical needs"

IO biomarker • Preclinical • Stroma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • IGH • MALT1

Co-Targeting BCL-2 and MCL1 (via CDK9) in Pre-Clinical Models of High-Risk Acute Lymphoblastic Leukemia (ASH 2024) - "Relapsed disease has poor prognosis, especially after immunotherapeutic approaches have failed, including blinatumomab (bispecific T cell engager BITE) and chimeric antigen receptor T-cell (CAR-T) therapy...Methods : Venetoclax, alvocidib, S63845 (MCL1i), dexamethasone and tyrosine kinase inhibitors (TKIs) were from Selleckchem...Conclusions : Simultaneous inhibition of BCL-2 and CDK9 represents an effective approach for targeting Ph+, KMT2AR and CD19-/- B-ALL without need for additional DNA-damaging chemotherapy or kinase inhibition. Taken together, this provides strong rationale for the clinical translation of venetoclax combined with alvocidib in patients with poor prognosis ALL, thereby offering a promising novel combination treatment for CAYA."

IO biomarker • Preclinical • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • CDK9 • KMT2A • PRKDC

Calaspargase-Pegol-Mknl Combined with BCL-2 and MCL-1 Inhibition for Acute Myeloid Leukemia. (PubMed, Int J Mol Sci) - "Our previous studies have demonstrated that pegcrisantaspase (PegC), a long-acting Erwinia asparaginase, synergizes with the BCL-2 inhibitor Venetoclax (Ven) in vitro and in vivo; however, the anti-leukemic activity of E. coli-derived asparaginases in combination with BCL-2 inhibition, and potential synergy with inhibitors of MCL-1, a key resistance factor of BCL-2 inhibition, has yet to be determined. Using a combination of human AML cells lines, primary samples, and in vivo xenograft mouse models, we established the anti-leukemic activity of the BCL-2 inhibitor S55746 and the MCL-1 inhibitor S63845, alone and in combination with the long-acting E. coli asparaginase calaspargase pegol-mknl (CalPegA)...The S55746-CalPegA combination inhibited protein synthesis and increased eIF4E/4EBP1 interaction, suggesting an inhibition of translational complex formation. These results support the clinical evaluation of CalPegA in combination with BCL-2 inhibition for AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • EIF4E • EIF4EBP1

Salinomycin Nanoparticles Induce Ferroptosis and Synergize with the BCL-2 Inhibitor Venetoclax to Promote AML Cell Death (ASH 2024) - "We treated human AML cell lines (MOLM-14, MOLM-13, MV4-11, HL-60, and THP-1) including venetoclax-resistant (VEN-R) THP-1 cells as well as primary AML blasts from patients with SAL-NP alone and in combination with decitabine, midostaurin, S63845 (MCL-1 inhibitor) and venetoclax and measured cell growth by trypan blue exclusion assay, cell death by propidium iodide (PI) staining and colony formation. SAL-NP in combination with VEN substantially reduced c-MYC and GPX4 levels and significantly induced cleavage of Caspase-3 and PARP compared with either agent alone.Conclusion : SAL-NP is a promising anti-AML agent. Its mechanism of action may involve the promotion of ferroptosis and increased dependency on BCL-2, which may account for the apparent activity in VEN-R cells and suggests the potential clinical benefit of combining SAL-NP with BCL-2 inhibitors."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CASP3 • GPX4 • MYC

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

Voltage-Dependent Anion Channel 2 Controls Mitochondrial Priming through BAK Stabilization in Multiple Myeloma (ASH 2024) - "Conversely, the transient silencing of VDAC2, while maintaining BAK protein levels, increased the global, MCL1 and BCL2 mitochondrial priming, induced BAK activation and in turn enhanced cell death induced by BH3 mimetics targeting MCL1 (S63845) or targeting BCL2 (venetoclax) in MM cells. Together these results provide evidence of the crucial role of VDAC2 in the regulation of mitochondrial apoptosis in myeloma cells through BAK control. Further investigations are conducted to elucidate if the VDAC2/BAK axis could have a potential therapeutic application in MM and other hematologic cancers, notably with the use of efsevin."

IO biomarker • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • BAK1 • BCL2 • VDAC1 • VDAC3

MCL1 Promotes Fatty Acid β-Oxidation in Therapy-Resistant AML through Cytoplasmic Sequestration of the Transcriptional Repressor IRF2BP2 (ASH 2024) - "Notably, targeting BCL2 with venetoclax (Ven) in combination with azacitidine (Aza) has clinically delivered significant responses in newly diagnosed AML patients...Furthermore, forced IRF2BP2 nuclear localization among Ven/Aza-resistant LSC, using BH3 mimetic S63845, resulted in the transcriptional repression of ACSL1 (2-fold, p<0.01, n=3)...Collectively, these data provide evidence for a novel mechanism by which MCL1 non-canonically drives IRF2BP2 cytoplasmic sequestration and subsequent activation of ACSL1, promoting fatty acid β-oxidation metabolism. Thus, the unique MCL1-driven loss of IRF2BP2 transcriptional repressive activity represents a critical component defining Ven/Aza-resistant AML which may offer alternative strategies for therapeutic intervention."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ACSL1 • BCL2 • IRF2 • MCL1

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

Characterizing and Targeting of BCL-2 Family Members in Nasopharyngeal Carcinoma. (PubMed, Head Neck) - "Our study demonstrates the therapeutic potential of combining cisplatin and S63845, which warrants further investigation."

IO biomarker • Journal • Hematological Disorders • Hematological Malignancies • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • BCL2 • BCL2L1 • MCL1

Osteosarcoma cells depend on MCL-1 for survival, and osteosarcoma metastases respond to MCL-1 antagonism plus regorafenib in vivo. (PubMed, BMC Cancer) - "Chemotherapy, consisting of doxorubicin, cisplatin and methotrexate (MAP) increased the 5-year osteosarcoma survival rate from 20% to approximately 60% by the 1980s...Patients whose disease fails to respond to MAP receive second-line treatments such as etoposide and, in more recent years, the kinase inhibitor regorafenib...Importantly, we found that inhibition of MCL-1 with the BH3-mimetic S63845 combined with regorafenib significantly prolonged the survival of mice bearing pulmonary osteosarcoma metastases. Together, our results highlight the importance of MCL-1 in osteosarcoma cell survival and present a potential therapeutic avenue that may improve metastatic osteosarcoma patient outcomes."

Journal • Preclinical • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • BCL2 • BCL2L1 • MCL1

Comprehensive functional evaluation of head and neck squamous cell carcinoma with BH3-profiling demonstrates apoptotic competency and therapeutic efficacy of BH3-mimetics. (PubMed, Oral Oncol) - "We assessed response to BH3 mimetics including ABT-263 (navitoclax), an inhibitor of Bcl-2/Bcl-xL/Bcl-w, and S63845, an inhibitor of Mcl-1, both as single agents and in combination. We found the combination to be highly synergistic in 2D culture and in 3D organoid models of HHNSCC. Given our findings that co-dependency on Bcl-xL and Mcl-1 is common, and co-inhibition of these molecules is synergistic for growth suppression in HNSCC cells, these results elucidate the therapeutic potential of BCL-xL and MCL-1 inhibition in HNSCC."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • BCL2 • BCL2L1 • BCL2L2

Construction and clinical significance of prognostic risk markers based on cancer driver genes in lung adenocarcinoma. (PubMed, Clin Transl Oncol) - "This study identified 11 effective biomarkers, DE-CDGs, which can predict LUAD prognosis and explored the biological significance of CDGs in LUAD prognosis, immunotherapy, and treatment."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

TUSPETINIB RETAINS NANOMOLAR POTENCY AGAINST AML CELLS ENGINEERED TO EXPRESS THE NRASG12D MUTATION OR SELECTED FOR RESISTANCE TO VENETOCLAX (EHA 2024) - P1/2 | "Cells with NRASG12D did not demonstrate resistance to the MCL-1inhibitor S63845; instead, modest expression of NRASG12D in clones A and C was associated with 4...4-foldhypersensitivity to the Raf inhibitor belvarafenib... NRASG12D mutation in R/R AML patients is associated with poor response. This studyindicates: 1) that the level of NRASG12D mutant protein rather than its presence alone is the key determinantof sensitivity to both TUS and VEN in the MV-4-11 FLT3-ITD model; and 2) the combination of TUS+VENovercomes any resistance to each agent. There is a strong rationale for combining TUS with VEN to treatNRASG12D AML given that: a) the drugs exhibit additivity in cytotoxic assays in both the wild type MV-4-11and the NRASG12D clones; b) low levels of NRASG12D protein do not cause resistance to either drug; c) thedevelopment of even high levels of VEN resistance does not cause resistance to TUS; and d) the previously-reported marked hypersensitivity to VEN that..."

IO biomarker • Acute Myelogenous Leukemia • Immunology • Oncology • BCL2 • FLT3 • JAK1 • JAK2 • SYK

A NEW HUMAN ACUTE MYELOID LEUKEMIA CELL LINE SDEY-AML1 WITH KMT2A-MLLT3, IKZF1-EVX1, P53, ETV6 GENE ALTERATIONS AND HIGH TUMORIGENICITY IN NSG MICE (EHA 2024) - "The cellline displayed resistance to various chemotherapeutic agents, except S63845, Chidamide, papista andOlverembatinid. Therefore, a new acute myeloid leukemia cell line SDEY-AML1** with KMT2A-MLLT3, IKZF1-EVX1, p53 andETV6 gene alterations and high tumorigenicity in NSG mice** has been established. This cell line may beutilized in the research and development of new agents targeting KMT2A-associated leukemia, making it avaluable tool in the study of leukemogenesis."

Preclinical • Acute Myelogenous Leukemia • Epstein-Barr Virus Infections • Hematological Malignancies • Leukemia • Oncology • ETV6 • IKZF1 • KMT2A • MLLT3

DUAL TARGETING OF MCL-1 AND SPHINGOLIPID METABOLISM: CAN IT BE A NOVEL APPROACH FOR AN EFFECTIVE TREATMENT OF ACUTE MYELOID LEUKEMIA? (EHA 2024) - "Specifically, we aimed to investigate the effects of combining S63845, an Mcl-1inhibitor, with either Fingolimod (S1PR antagonist), ABC294640 (Opaganib, SPHK2 inhibitor), or Carmofur(ASAH1 inhibitor) regarding the cell proliferation, cell death, and, notably, on the lipidome via shotgunlipidomics in MV4-11, KG1 and HL60 human AML cell lines. Shotgun lipidomics results showed that S63845 + Opaganib combination altered the lipidome more than theother drug combinations, confirming the data from the cell proliferation and combination index analyses. Overall, our results suggest that dual targeting of Mcl-1 and SPHK2 might be an effective approach in AMLtreatment."

IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Mantle Cell Lymphoma • Metabolic Disorders • Oncology • ASAH1 • BCL2 • CASP3 • IL6 • SPHK1 • SPHK2 • TGFB1 • TNFA

Unveiling the Impact of Diffuse Intrinsic Pontine Glioma (DIPG) on Blood-Brain Barrier Integrity and Drug Penetration (EACR 2024) - "A more potent and selective MCL-1 inhibitor, S64315, also exhibited effects on BBB permeability in vitro, with significant changes to ZO-1 and claudin-5 expression...Toxicity studies have shown that repeated doses of S63845 with temsirolimus over 6 weeks is well tolerated...MCL-1 inhibitors may facilitate delivery of therapeutics by opening the BBB. This discovery has the potential to enhance the efficacy of anti-DIPG therapeutics."

Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • CLDN5 • TJP1

Metformin as an Enhancer for the Treatment of Chemoresistant CD34+ Acute Myeloid Leukemia Cells. (PubMed, Genes (Basel)) - "Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells. Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD14 • CD31 • CD34 • CD38 • CD9 • ENG • ITGAM • PECAM1