- |||||||||| Asparlas (calaspargase pegol-mknl) / Servier, Takeda, Leadiant Biosci
Journal: Calaspargase-Pegol-Mknl Combined with BCL-2 and MCL-1 Inhibition for Acute Myeloid Leukemia. (Pubmed Central) - Dec 17, 2024
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.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, salinomycin (HSB-1216) / Tharimmune
Salinomycin Nanoparticles Induce Ferroptosis and Synergize with the BCL-2 Inhibitor Venetoclax to Promote AML Cell Death () - Dec 7, 2024 - Abstract #ASH2024ASH_7901;
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.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, HitGen
Voltage-Dependent Anion Channel 2 Controls Mitochondrial Priming through BAK Stabilization in Multiple Myeloma (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5386;
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.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie
Integrative Analysis of Transcriptomic and Proteomic Data Identifies Patterns of Primary Resistance to Venetoclax-Azacitidine and Reveals Targetable Vulnerabilities in Acute Myeloid Leukemia (AML) (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5274;
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.
- |||||||||| Co-Targeting BCL-2 and MCL1 (via CDK9) in Pre-Clinical Models of High-Risk Acute Lymphoblastic Leukemia (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5196;
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.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie
Mechanistic Insights and Therapeutic Potential of a PRMT5 Inhibitor Combined with Venetoclax in B Cell Malignancies (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_4960;
P1, P1/2
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.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, HitGen
MCL1 Promotes Fatty Acid ?-Oxidation in Therapy-Resistant AML through Cytoplasmic Sequestration of the Transcriptional Repressor IRF2BP2 (Room 6A (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_2221;
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 ?-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.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, HitGen, ABT-737 / AbbVie
Journal, IO biomarker: Characterizing and Targeting of BCL-2 Family Members in Nasopharyngeal Carcinoma. (Pubmed Central) - Oct 30, 2024
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. Our study demonstrates the therapeutic potential of combining cisplatin and S63845, which warrants further investigation.
- |||||||||| Journal, IO biomarker: Construction and clinical significance of prognostic risk markers based on cancer driver genes in lung adenocarcinoma. (Pubmed Central) - Sep 20, 2024
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. 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.
- |||||||||| metformin / Generic mfg.
Journal, IO biomarker: Metformin as an Enhancer for the Treatment of Chemoresistant CD34+ Acute Myeloid Leukemia Cells. (Pubmed Central) - May 25, 2024
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.
- |||||||||| dorsomorphin (Compound C) / EMD Serono
Journal, IO biomarker: AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death. (Pubmed Central) - Mar 28, 2024
BH3 mimetics, including the BCL2/BCLXL/BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms...Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors...Conversely, dorsomorphin synergizes with navitoclax or the MCL1 inhibitor S63845 to induce cell death in primary acute leukemia samples ex vivo and increases the antitumor effects of navitoclax or S63845 in several xenograft models in vivo with little or no increase in toxicity in normal tissues. These results suggest that AMPK inhibition can sensitize acute leukemia to multiple BH3 mimetics, potentially allowing administration of lower doses while inducing similar antineoplastic effects.
- |||||||||| S63845 / Servier, Novartis, HitGen
Effect of MCL-1 inhibitor on organoids derived from cholangiocarcinoma patients with IDH1 mutation (Section 9) - Mar 5, 2024 - Abstract #AACR2024AACR_3156;
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.
- |||||||||| S63845 / Servier, Novartis, HitGen
Journal, IO biomarker: A p53 score derived from TP53 CRISPR/Cas9 HMCLs predicts survival and reveals major role of BAX in BH3 mimetics response. (Pubmed Central) - Dec 14, 2023
At the functional level, we showed that among the 13 genes, p53-regulated BAX expression correlated to, and directly impacted, the MCL1 BH3 mimetic S63845 sensitivity of myeloma cells by decreasing MCL1-BAX complexes...Nevertheless, scRNAseq analysis showed that myeloma cells surviving to the combination had lower p53 score, showing that myeloma cells with higher p53 score were more sensitive to BH3 mimetics. Taken together, we established a functional p53 score that identifies myeloma cells with biallelic TP53 invalidation, demonstrated that p53-regulated BAX is critical for optimal cell response to BH3 mimetics, and showed that MCL1 and BCL2 BH3 mimetics combination may be of interest for patients with biallelic TP53 invalidation, for whom there is still an unmet medical need.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Walter and Eliza Hall Institute, S63845 / Servier, Novartis, HitGen
Journal: Statin-induced mitochondrial priming sensitizes multiple myeloma cells to BCL2 and MCL1 inhibitors. (Pubmed Central) - Nov 13, 2023
Statins sensitize MM cells to venetoclax by upregulating two pro-apoptotic proteins: PUMA via a p53-independent mechanism, and NOXA via the integrated stress response. These findings provide rationale for prospective testing of statins with venetoclax regimens in MM.
- |||||||||| DT2216 / Dialectic Therap
Targeting BCL-XL with a Novel VHL-Based BCL-XL Degrader DT-2216 in Pre-Clinical JAK2-Mutant AML Post-MPN Models (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_5583;
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.
- |||||||||| navitoclax (ABT 263) / AbbVie
Pre-Clinical Activity of Navitoclax in TCR-Driven and Non-ALCL Mature T-Cell Lymphomas (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_5574;
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.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Walter and Eliza Hall Institute, S63845 / Servier, Novartis, HitGen
Targeting ADSS2 Enhances BH3 Mimetics Treatment Induced Mitochondrial Apoptosis in AML Cells (Marriott Marquis - Marriott Grand) - Nov 3, 2023 - Abstract #ASH2023ASH_3253;
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.
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Journal, Combination therapy, IO biomarker: HSP90 Inhibitor PU-H71 in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia. (Pubmed Central) - Sep 27, 2023
Elevated susceptibility to PU-H71 and venetoclax was associated with primary AML with CD117 > 80% and CD11b < 45%. The combination of HSP90 inhibitor PU-H71 and MCL1 inhibitor S63845 may be a candidate treatment for FLT3-mutated AML with moderate CD34 positivity while the combination of HSP90 inhibitor PU-H71 and BCL2 inhibitor venetoclax may be more effective in the treatment of primitive AML with high CD117 and low CD11b positivity.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Walter and Eliza Hall Institute, S63845 / Servier, Novartis, HitGen
Journal: Intracellular BAPTA directly inhibits PFKFB3, thereby impeding mTORC1-driven Mcl-1 translation and killing MCL-1-addicted cancer cells. (Pubmed Central) - Sep 13, 2023
Previously, we demonstrated that BAPTA enhanced apoptosis induced by venetoclax, a BCL-2 antagonist, in diffuse large B-cell lymphoma (DLBCL)...In this study, we discovered that BAPTA alone induced apoptosis in hematological cancer cell lines that were highly sensitive to S63845, an MCL-1 antagonist...Secondly, cellular effects caused by BAPTA are not necessarily related to Ca signaling. Our data support the need for a reassessment of the role of Ca in cellular processes when findings were based on the use of BAPTA.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Walter and Eliza Hall Institute
Acquisition of venetoclax resistance is characterized by higher expression of anti-apoptotic regulators, less mitochondrial priming, and broader resistance to anti-MM agents. (In Person) - Sep 10, 2023 - Abstract #IMW2023IMW_465;
The Bellini study demonstrated that combination therapy of BH3-mimetic venetoclax with velcade improves progression-free survival (PFS) and response rates in this subgroup of MM patients...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. In conclusion, we report that resistance to Venetoclax in in vitro models of MM evolves from the outgrowth of persister clones with a shift in mitochondrial dependency that confers broad resistance to all anti-tumor agents, including standard-of-care myeloma drugs.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Walter and Eliza Hall Institute, S63845 / Servier, Novartis, HitGen, AZD5991 / AstraZeneca
Characterizing Specificities of Chronic Lymphoid Leukemia Harboring a BCL2 Rearrangement, an update from the FILO group () - Aug 14, 2023 - Abstract #IWCLL2023IWCLL_244;
The genomic landscape of BCL2-R CLL is characterized by a high frequency of trisomy 12, subclonal NOTCH and RAS pathway mutations, as well as BCL2 and MLL2 mutations. Protein expression, BH3 profiling and viability assays data are consistent with nearly exclusive dependence on Bcl-2.
- |||||||||| S63845 / Servier, Novartis, HitGen
Journal: AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosis. (Pubmed Central) - May 28, 2023
Knockdown of BAD significantly inhibits MK-2206-induced sensitization to S63845. Thus, our results suggest that MK-2206 sensitizes multiple leukemia cells to S63845-induced apoptosis, with the mechanisms involving BAD dephosphorylation and BCLX downregulation.
- |||||||||| CLL Targets Beyond BTKi and Bcl2i (HALL A) - May 20, 2023 - Abstract #ICLLM2023ICLLM_55;
Meanwhile, we have shown that luxeptinib, a dual SYK/BTK kinase inhibitor, has activity in BTK inhibitor-resistant lymphoid models in vitro.5 Luxeptinib is now being investigated in lcinical trials in hematologic malignancies...The early results of MS-553, a selective PKC-? inhibitor, indicates that this agent is tolerable and effective both as single agent and in combination with venetoclax.8 Proteolysis-targeting chimeras (PROTACs) are a new class of small molecules with two covalently-linked ligands recruiting target protein and E3 ubiquitin ligase together to trigger and enable proteasomal degradation of the target protein.9
- |||||||||| S63845 / Servier, Novartis, HitGen
Journal: SARS-CoV-2 N protein enhances the anti-apoptotic activity of MCL-1 to promote viral replication. (Pubmed Central) - May 14, 2023
Importantly, N protein promoted the replications of IAV, DENV and ZIKV, and exacerbated death of IAV-infected mice, all of which could be blocked by a MCL-1 specific inhibitor, S63845...These may explain how SARS-CoV-2 effectively replicates in asymptomatic individuals without cuasing respiratory dysfunction, and indicate a risk of enhanced coinfection with other viruses. We anticipate that abrogating the N/MCL-1-dominated apoptosis repression is conducive to the treatments of SARS-CoV-2 infection as well as coinfections with other viruses.
- |||||||||| S63845 / Servier, Novartis, HitGen
MCL-1 INHIBITION AFFECTS LIPIDOME WHICH MAY BE LINKED TO TUMOR IMMUNITY AND CANCER-RELATED INFLAMMATION IN ACUTE MYELOID LEUKEMIA () - May 12, 2023 - Abstract #EHA2023EHA_2589;
Additionally, the study highlights that S63845 has a distinct impact on the lipid profiles of different AML cell lines, indicating the potential of using lipidomic profiles asmarkers. Importantly, our study proposes that the increases in Cer levels in response to S63845 treatment may occur due to SM hydrolysis and may be linked to the anti-inflammatory effects of S63845 in AML cell lines, which deserve further investigation to fully understand the specific mechanisms.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Walter and Eliza Hall Institute
BCL-2/BCL-XL INHIBITION INDUCES APOPTOSIS AND CIRCUMVENTS VENETOCLAX RESISTANCE IN TP53-MUTATED ACUTE MYELOID LEUKEMIA (Poster area) - May 12, 2023 - Abstract #EHA2023EHA_1845;
P2
In contrast, our BH3 mimetic drug screening results demonstrated that the dual inhibition of BCL-2 and BCL-XL by navitoclax is capable of inducing apoptosis in myeloid blast cells regardless of TP53 mutation status. However, larger patient cohorts and more extensive functional analysis of the anti/pro-apoptotic dependencies in this patient group is warranted.
- |||||||||| S63845 / Servier, Novartis, HitGen
Journal: MCL-1 Inhibitor S63845 Distinctively Affects Intramedullary and Extramedullary Hematopoiesis. (Pubmed Central) - Apr 28, 2023
The maturation of the erythroid lineage in the intramedullary and extramedullary segments was blocked to varying degrees, and both the intramedullary and extramedullary lymphoid lineages were inhibited. This study provides a complete description of the effects of MCL-1 inhibitor on the intramedullary and extramedullary hematopoietic lineages, which is important for the selection of combinations of antitumor drugs and the prevention of adverse hematopoiesis-related effects.
- |||||||||| S63845 / Servier, Novartis, HitGen, navitoclax (ABT 263) / AbbVie
Journal, Combination therapy: Synergistic combination therapy delivered via layer-by-layer nanoparticles induces solid tumor regression of ovarian cancer. (Pubmed Central) - Mar 17, 2023
Thus, these results support the exploration of LbL NPs as a strategy to deliver potent drug combinations to recurrent HGSOC. While these findings are described for co-encapsulation of a BCL2/XL and a MCL1 inhibitor, the modular nature of LbL assembly provides flexibility in the range of therapies that can be incorporated, making LbL NPs an adaptable vehicle for delivery of additional combinations of pathway inhibitors and other oncology drugs.
- |||||||||| S63845 / Servier, Novartis, HitGen, SCH772984 / Otsuka, Zelboraf (vemurafenib) / Roche
Journal, PARP Biomarker, IO biomarker: Enhanced Apoptosis and Loss of Cell Viability in Melanoma Cells by Combined Inhibition of ERK and Mcl-1 Is Related to Loss of Mitochondrial Membrane Potential, Caspase Activation and Upregulation of Proapoptotic Bcl-2 Proteins. (Pubmed Central) - Mar 16, 2023
The combination finally resulted in downregulation of antiapoptotic Bcl-2 and enhanced expression of the proapoptotic Noxa. In conclusion, combined inhibition of ERK and Mcl-1 revealed an impressive efficacy both in BRAF-mutated and WT melanoma cells, and may thus represent a new strategy for overcoming drug resistance.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, MIK-665 / Novartis, HitGen, Epidaza (chidamide) / Chipscreen, Meiji Seika, Eisai, HUYA Bioscience
Review, Journal: The Role of BCL-2 and PD-1/PD-L1 Pathway in Pathogenesis of Myelodysplastic Syndromes. (Pubmed Central) - Mar 16, 2023
P1b
Molecules with the potential to break the associated resistance include S63845, S64315, chidamide and arsenic trioxide (ATO)...Knockdown of the PD-L1 gene in preclinical studies was associated with increased levels of BCL-2 and MCL-1 in lymphocytes T, which could increase their survival and promote tumor apoptosis. A trial (NCT03969446) is currently underway to combine inhibitors from both groups.
- |||||||||| S63845 / Servier, Novartis, HitGen, Blincyto (blinatumomab) / Astellas, Amgen, Koselugo (selumetinib) / Merck (MSD), AstraZeneca
Use of luciferase-labeled target cells to explore immune cell killing in high throughput format in 2D and 3D co-cultures (Section 40; Poster Board #5) - Mar 14, 2023 - Abstract #AACR2023AACR_5858;
Depending on compound combination, we observe synergistic (e.g. Lenalidomide) but also antagonistic effects (e.g. MEK-inhibitor, Selumetinib, and MCL-1-inhibitor, S63845)...Moreover, we show an ADCC example using NK as cytotoxic cells. Our data supports the outstanding usefulness of this methodological approach for the exploration of the overall efficiency of a therapy to enhance tumor cell killing by immune effector cells.
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