S63845 / Servier, Novartis, HitGen - LARVOL DELTA

Synergistic vulnerability of aggressive B-cell lymphoma to combined MCL-1 inhibition and CAR-T cell therapy (ASH 2025) - "In this study, we identify that drug-tolerant persister (DTP) cells and therapy-resistant lymphoma cells persist within a highly immunogenic tumor microenvironment (TME) that emerges following treatment with the MCL-1 inhibitor S63845...Overall, our findings support a synergistic dual-targeting strategy that addresses both tumor-intrinsic survival mechanisms and the immunosuppressive TME. This combinatorial "one-two punch" approach holds strong potential for eliminating minimal residual disease, preventing relapse, and achieving sustained clinical remissions in aggressive B-cell lymphomas."

CAR T-Cell Therapy • IO biomarker • B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • MYC • STAT1

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

Dissection of non-genetic resistance mechanisms by lineage tracing and single cell multiomics reveals drug-specific persister programs in Acute Myeloid Leukemia (ASH 2025) - "Ourdata showed the emergence of slow cycling persisters with cytarabine (AraC) in all 4 cell lines, andgilteritinib (GLT) in MOLM-13 and MV4-11 cells while BH3 mimetics (venetoclax (VEN), S63845 andnavitoclax) had fast-cycling persisters. We next asked whichmotifs are highly enriched in each persister and observed the enrichment of various KLF and SP family ofmotifs in each persister driving multiple gene signatures in each persister type. We also observedenrichment of LSC-primed and cDC like cells in GLT persisters but with AraC and VEN persisters auniform pattern of all states was observed, indicated stemness may not be common mechanism topersister evolution.Collectively, our integrated single-cell multiomics and lineage tracing approach reveals that AMLpersisters emerge through stochastic drug-specific, non-genetic adaptive mechanisms characterized bydistinct transcriptional and chromatin remodeling programs rather than deterministic Darwinianselection of pre-existing..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • TNFA

PPM1D mutations confer resistance to venetoclax in pre-leukemic and AML populations (ASH 2025) - "In long-term co-culture assays,PPM1Dmut cells were competitively enriched, compared to WT cells upon exposure to eitherchemotherapy (Ara-C or 5-FU) or VEN...VEN combined with either small molecule PPM1D (GSK-2830371) or MDM2inhibitors (RG-7388) showed promising efficacy against PPM1Dmut, but were ineffective against TP53KOcells. In contrast, VEN + MCL1 inhibitor (S63845) was highly cytotoxic and efficacious across all genotypestested, including both PPM1Dmut and TP53KO cells...PPM1Dmutlikely arises in pre-leukemic or leukemic cells selected toexpand during VEN exposure. Resistance to VEN mediated by PPM1D abnormalities appeared to be TP53dependent and alleviated by combining VEN with MCL1 inhibition, which may also have clinical rationalein pts harboring concurrent PPM1D and TP53 mutant disease."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • FLT3 • KRAS • PPM1D • PTPN11

A combination strategy of inotuzumab ozogamicin (InO) and BCL-2 family inhibitors prevents the emergence of PGP+ ino-resistant MRD in B-cell acute lymphoblastic leukemia (ASH 2025) - "Venetoclax (VEN) and navitoclax, not S63845(Mcl1 inhibitor) synergized with InO to enhance the killing of ALL cells. While InO therapy achieves high remission rates, it may induce the emergence of InO-R/Pgp+ALL cells as residual disease. Combination therapy with InO and Bcl-2 family inhibitors may effectivelysuppress the emergence of these InO-resistant clones, thereby prolonging remission duration."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • ABCB1 • CD22

The development of ACT001 with Mcl-1 inhibitors as a novel combination therapy for the treatment of paediatric diffuse midline glioma (SNO 2025) - P1 | "Among the strongest were Mcl-1 inhibitors (Mcl1i-MIK665, Mcl1i-AZD5991) consistent with ACT001's mechanism of downregulating anti-apoptotic signaling...In vivo, single-drug treatment of ACT001 or Mcl1i-S63845 extended survival in orthotopic DMG models and significantly reduced the number of Ki67-positive tumor cells...Our findings suggest that ACT001 is a multi-targeted agent acting on NF-κB and apoptotic signalling while inducing oxidative stress. The combination of ACT001 with anti-apoptotic protein inhibitors represents a promising treatment strategy for DMG patients."

Combination therapy • IO biomarker • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • Pediatrics • Solid Tumor • BCL2 • NQO1 • SLC7A11 • SOD2

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

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

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

The development of ACT001 with Mcl-1 inhibitors as a novel combination therapy for the treatment of paediatric diffuse midline glioma (WFNOS 2025) - P1 | "Among the strongest were Mcl-1 inhibitors (Mcl1i-MIK665, Mcl1i-AZD5991) consistent with ACT001’s mechanism of downregulating anti-apoptotic signaling...In vivo, single-drug treatment of ACT001 or Mcl1i-S63845 extended survival in orthotopic DMG models and significantly reduced the number of Ki67-positive tumor cells...Our findings suggest that ACT001 is a multi-targeted agent acting on NF-κB and apoptotic signalling while inducing oxidative stress. The combination of ACT001 with anti-apoptotic protein inhibitors represents a promising treatment strategy for DMG patients."

Combination therapy • IO biomarker • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • Pediatrics • Solid Tumor • BCL2 • NQO1 • SLC7A11 • SOD2

Venetoclax Resistance Results in Broad Resistance to Majority of Anti-MM Agents Due to the Suppression of Apoptosis but Can be Overcome By BCMA-Targeted Immunotherapy (ASH 2023) - "We observed that venetoclax-resistant clones were resistant to most standard-of-care anti-MM agents including alkylating agents (Melphalan, cyclophosphamide, bendamustine), proteasome inhibitors (bortezomib and carfilzomib) or immunomodulatory drugs (lenalidomide and pomalidomide) than parental cells, suggesting a broad resistance to anti-cancer agents possibly due to reduced apoptotic signaling...Simultaneous inhibition of MCL1 (via S63845) or BCL-XL (via A155463) and BCL2 (via venetoclax) increased BIM release and enhanced cell death in the resistant clones compared to single agents, with combination index (CI) values < 0.3 in all doses tested...We observed that both antibody-dependent cellular cytotoxicity (ADCC) induced by Daratumumab and BCMA targeting CAR-T cells induced comparable cell death in venetoclax-resistant clones and parental cells. Moreover, myeloma cells from a patient with t(11; 14) MM progressing on venetoclax, showed significant cytotoxicity to..."

IO biomarker • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Oncology • BCL2 • BCL2L1 • BCL2L2

Targeting BCL-XL with a Novel VHL-Based BCL-XL Degrader DT-2216 in Pre-Clinical JAK2-Mutant AML Post-MPN Models (ASH 2023) - "However, the clinical utility of navitoclax, a BCL-xL and BCL-2 dual inhibitor, as demonstrated in combination with JAK2 inhibitor ruxolitinib in patients with myelofibrosis (Harrison et al...In this study, we evaluated the pre-clinical efficacy of DT2216 in combination with ruxolitinib, 5-azacytidine (AZA), or MCL-1 inhibitor S63845 in JAK2-mut AML models...CONCLUSIONS These findings highlight the promising efficacy of DT2216 in JAK2-mut AML, as evidenced by reduced cell viability, on-target degradation of BCL-xL, and synergistic anti-leukemia effects when combined with AZA, ruxolitinib or MCL-1 inhibitor. These results provide valuable insights into future therapeutic strategies for the treatment of JAK2-mut AML, particularly in the context of post-MPN AML."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Targeted Protein Degradation • Thrombocytopenia • BCL2L1 • JAK2

Pre-Clinical Activity of Navitoclax in TCR-Driven and Non-ALCL Mature T-Cell Lymphomas (ASH 2023) - P2 | "In an effort to further confirm these results, and examine the extent to which peptide-based BH3 profiling predicts sensitivity to selective BH3 mimetics in MTCL, cell lines were treated with venetoclax, A1155463 (a BCL-xL selective antagonist), navitoclax (a BCL-2/BCL-xL antagonist), or S63845 (MCL-1 antagonist), and cell viability determined. These findings suggest that BCL-xL is a therapeutic vulnerability for MTCL subsets, particularly non-ALCL subtypes that are TCR dependent, and provide a robust pre-clinical rationale for future studies investigating navitoclax in these lymphomas."

IO biomarker • Preclinical • B Cell Lymphoma • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Acute Lymphoblastic Leukemia • T Cell Non-Hodgkin Lymphoma • BCL2 • BCL2L1 • BCL2L2 • CD28 • MCL1

FRET two-hybrid assay-based target drug screening in living cells. (PubMed, J Biotechnol) - "The FRET-HBTDS method was performed on the FRETscope with a 20× objective for the cells co-expressing CFP-Bcl-xL and YFP-Bak to assess the action of eight compounds (A1331852, S63845, AC, DSF/Cu, Met, REGO, SOFA, ABT199) on the interaction between Bcl-xL and Bak. Our data firmly demonstrate that A1331852 unlocks the binding state of Bcl-xL and Bak, while DSF/Cu modifies the structure of the Bcl-xL-Bak complex. These findings demonstrate that FRET-HBTDS can be used to assess the efficacy of a drug by revealing the binding state and complex molecular structure of the target proteins using FRET technology in living cells, which may be a potential targeted drug screening method."

Journal • Oncology • BCL2L1 • CFP

Long-Acting E. coli-Derived Asparaginase Potentiates the Anti-Leukemic Effect of BCL2 Inhibition, but Not MCL1 Inhibition, in Preclinical Models of Acute Myeloid Leukemia (ASH 2023) - "Our previous studies have shown that pegcrisantaspase (PegC), a long-acting pegylated crisantaspase, synergizes with the BCL2 inhibitor, Venetoclax (Ven), to kill several AML cell lines and patient-derived primary AML cells with complex karyotype in vitro and in vivo in a xenograft mouse model... Using a panel of 4 human AML cell lines (MOLM14, MV411, MonoMac6, HL60) as well as primary AML patient samples, weestablished the anti-leukemic activity of the BCL2 inhibitor S55746 and the MCL1 inhibitor S63845 alone and in combination with the long-acting E. coli asparaginase, calaspargase pegol-mknl (CalPegA)... We report that the E. coli asparaginase, CalPegA, enhances the anti-leukemic effect of the BCL2 inhibitor, S55746, but does not impact the activity of the MCL1 inhibitor, S63845, in AML cell lines, patient derived primary AML samples, and in an AML xenograft mouse model. Ongoing studies are further investigating the anti-leukemic mechanism of S55476/S63845 + CalPegA..."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • 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

Targeting ADSS2 Enhances BH3 Mimetics Treatment Induced Mitochondrial Apoptosis in AML Cells (ASH 2023) - "Recently, the BH3 mimetic-Bcl2 inhibitor venetoclax (VEN), has been approved by FDA in 2018 for the treatment of patients with AML in combination with a hypomethylating agent (HMA) such as azacytidine (AZA)...ADSS2 KO also led to a noteworthy reduction in the IC50 values of both VEN and the Mcl1 inhibitor S63845 in these cell lines...Collectively, our observation revealed that targeting ADSS2 is critical for sensitizing AML cells to BH3 mimetics. We are now conducting preclinical assessments of ADSS2 inhibitors."

IO biomarker • Acute Myelogenous Leukemia • Oncology • PRKAA2

Acquired Venetoclax Resistance in an In Vivo Model of B-Cell Precursor Acute Lymphoblastic Leukemia Is Characterized By Altered Functions of Apoptosis Regulators (ASH 2023) - "This shift was also reflected in an ex vivo drug treatment assay showing decreased sensitivity to the MCL-1 inhibitor S63845 and the BCL-XL inhibitor A-1331852 in ALL cells from VEN- treated mice compared to control- treated mice (S63845 EC50 1.5 vs. 2.2 µM, A-1331852 EC50 9.3 vs. 15.3 µM). Taken together, acquired VEN-resistance was recapitulated in a co-clinical trial model of BCP-ALL with repeated in vivo treatment cycles showing lower drug sensitivities along with increasingly reduced in vivo anti-ALL activity of VEN. Characterization of acquired VEN-resistance revealed decreased functional dependency on anti-apoptotic proteins and downregulation of pro-apoptotic BIM and BAX, thus pointing to an imbalance of pro- and anti-apoptotic molecules, which can be potentially targeted by directed compounds bypassing resistance to specific BCL-2 inhibition."

IO biomarker • Preclinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • KMT2A

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 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

Combining BCL-XL Inhibition with Brentuximab Vedotin to Overcome Chemoresistance in EBV-Related T/NK Lymphoma (ASH 2023) - "MethodsA diverse panel of EBV+ T/NK lymphoma cell lines including SNK1, MECO4, SNK6, SNT8, SNK10, SNT15 and SNT16 were evaluated for sensitivity to MMAE alone and with specific BH3 family inhibitors including A1331852, inhibiting BCL-XL, venetoclax inhibiting and BCL-2 and the MCL-1 inhibitor S63845 (Generon). These data show the potential of BV with BCL-XL inhibition to be an effective and tolerable treatment for ENKTL. We are now planning a detailed preclinical study to better understand the efficacy and safety of this combination in vivo and progress towards a future clinical trial."

IO biomarker • Epstein-Barr Virus Infections • Extranodal Natural Killer/T-cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Natural Killer/T-cell Lymphoma • Oncology • Thrombocytopenia • BCL2 • BCL2L1 • TNFRSF8

Drug Resistance Can be Overcome in Multiple Myeloma and Acute Myeloid Leukemia By Targeting Mcl-1 with the Small Chemical KS18 (ASH 2023) - "5µM, KS18 demonstrated efficacy against bortezomib-resistant MM cells, outperforming other Mcl-1 inhibitors in clinical trials such as S63845, VU661013, and AZD5991. According to these results, KS18 may be able to overcome resistance by concentrating on Mcl-1. These encouraging findings have prompted the development of many models of drug-resistant MM and AML for in vivo evaluation of this potential chemical."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • BCL2

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