- |||||||||| Venclexta (venetoclax) / Roche, AbbVie
Journal, IO biomarker: Venetoclax-based rational combinations are effective in models of MYCN-amplified neuroblastoma. (Pubmed Central) - Feb 19, 2022
P1
Finally, the standard-of-care drug cocktail cyclophosphamide and topotecan reduces the apoptotic threshold of neuroblastoma, thus setting the stage for robust combination efficacy with venetoclax...Venetoclax is currently being evaluated in pediatric patients in the clinic, including neuroblastoma (NCT03236857). While establishment of safety is still ongoing, the data disclosed herein indicate rational and clinically actionable combination strategies that could potentiate the activity of venetoclax in MYCN-amplified NB patients.
- |||||||||| Journal: Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells. (Pubmed Central) - Feb 19, 2022
FASN inhibition, however, fails to sensitize breast cancer cells to MCL-1- and BCL-X-selective inhibitors such as S63845 and A1331852...In summary, a novel FASN-driven facet of the mitochondrial priming mechanistically links the redox-buffering mechanism of FASN activity to the intrinsic apoptotic threshold in breast cancer cells. Combining next-generation FASNis with BCL-2-specific BH3 mimetics that directly activate the apoptotic machinery might generate more potent and longer-lasting antitumor responses in a clinical setting.
- |||||||||| Journal: Peptide and Small Molecule Inhibitors Targeting Myeloid Cell Leukemia 1 (Mcl-1) as Novel Antitumor Agents. (Pubmed Central) - Feb 11, 2022
In this review, we summarize the recent literature on small molecule and peptide inhibitors of Mcl-1, which are divided into different types including: peptide inhibitors, gossypol derivatives, marinopyrrole derivatives, S1 derivatives, indole derivatives, quinoline derivatives, S63845, AZD5991, AMG176, etc. Their biological activities are also summarized. Mcl-1 is a valid drug target and inhibition of Mcl-1 with a small molecule inhibitor is a promising strategy for cancer therapy.
- |||||||||| S63845 / Servier, Novartis, Ligand
Journal: Constitutive BAK/MCL1 complexes predict paclitaxel and S63845 sensitivity of ovarian cancer. (Pubmed Central) - Jan 27, 2022
Further studies indicated that cells with preformed BAK/MCL1 complexes were sensitive to the paclitaxel/S63845 combination, while cells without BAK/MCL1 complexes were not. Our study suggested that the assessment of BAK/MCL1 complexes might be useful for predicting response to paclitaxel alone or in combination with BH3 mimetics.
- |||||||||| daporinad (APO866) / Onxeo, S63845 / Servier, Novartis, Ligand
Journal: Metabolic perturbations sensitize triple-negative breast cancers to apoptosis induced by BH3 mimetics. (Pubmed Central) - Jan 14, 2022
We found that NAMPT inhibition reduced NAD concentrations below a critical threshold that resulted in depletion of adenine, which was the metabolic trigger that primed TNBC cells for apoptosis. These findings demonstrate a close interaction between metabolic and mitochondrial apoptotic signaling pathways and reveal that exploitation of a tumor-specific metabolic vulnerability can sensitize some TNBC to BH3 mimetics.
- |||||||||| S63845 / Servier, Novartis, Ligand
Preclinical, Journal: Bak and Bcl-xL Participate in Regulating Sensitivity of Solid Tumor Derived Cell Lines to Mcl-1 Inhibitors. (Pubmed Central) - Jan 12, 2022
We investigated two BH3 mimetics to Mcl-1, A1210477 and S63845, and found their different efficacies in on-target doses, despite the fact that both agents interacted with the target...Surprisingly, in Bak-knockout cells, inhibition of Mcl-1 and Bcl-xL still resulted in pronounced cell death, arguing against a sole role of Bak in the studied phenomenon. We demonstrate that Bak and Bcl-xL are co-factors for, respectively, sensitivity and resistance to Mcl-1 inhibition.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, Ligand, A-1331852 / AbbVie
Clinical, Journal: Pediatric multicellular tumor spheroid models illustrate a therapeutic potential by combining BH3 mimetics with Natural Killer (NK) cell-based immunotherapy. (Pubmed Central) - Jan 12, 2022
Treatment with either the Bcl-X inhibitor A1331852 or the Mcl-1 inhibitor S63845 increased the cytotoxicity of NK cells and reduced spheroid size, while the Bcl-2 inhibitor ABT-199 had no effect on NK cell-mediated killing. Taken together, this is the first study to describe the combination of BH3 mimetics targeting Bcl-X or Mcl-1 with NK cell-based immunotherapy, highlighting the potential of BH3 mimetics in immunotherapy.
- |||||||||| Nutlin-3 / EMD Serono, S63845 / Servier, Novartis, Ligand
Characterising the role of ARRDC3 as a regulator of P53-mediated apoptosis () - Jan 7, 2022 - Abstract #LCC2022LCC_120;
ARRDC3 is a poorly studied gene, but the best-known functionality for other arrestin family genes is involvement in G-protein coupled receptor ubiquitination and degradation. We are aiming to elucidate the function of ARRDC3 in organismal development and apoptosis, and identify whether it has potential as a drug target for cancer therapy.
- |||||||||| sirolimus / Generic mfg.
Journal, IO biomarker: Synergistic melanoma cell death mediated by inhibition of both MCL1 and BCL2 in high-risk tumors driven by NF1/PTEN loss. (Pubmed Central) - Jan 1, 2022
Because addition of the BCL2 inhibitor venetoclax resulted in compensatory upregulation of MCL1, we established a three-drug combination composed of sirolimus, venetoclax, and the MCL1 inhibitor S63845. This well-tolerated drug combination potently and synergistically induces apoptosis in both zebrafish and human NF1/PTEN-deficient melanoma cells, providing preclinical evidence justifying an early-stage clinical trial in patients with NF1/PTEN-deficient melanoma.
- |||||||||| S63845 / Servier, Novartis, Ligand, ulixertinib (BVD-523) / BioMed Valley Discoveries
Journal, IO biomarker: Co-targeting MCL-1 and ERK1/2 kinase induces mitochondrial apoptosis in rhabdomyosarcoma cells. (Pubmed Central) - Dec 16, 2021
Overexpression of BCL-2 rescues cell death triggered by Ulixertinib/S63845 co-treatment, confirming that combined inhibition of ERK1/2 and MCL-1 effectively induces cell death of RMS cells via the intrinsic mitochondrial apoptotic pathway. Thus, this study is the first to demonstrate the cytotoxic potency of co-inhibition of ERK1/2 and MCL-1 for RMS treatment.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, Ligand
Journal: Tumor Targeted Nanoparticles Improve Therapeutic Index of BCL2 and MCL1 dual inhibition. (Pubmed Central) - Dec 16, 2021
Furthermore, nanoparticle encapsulation allowed 3.5 to 6.5-fold reduction in drug dose, induced sustained remissions and minimized toxicity. Our results support the development of nanoparticles to deliver BH3 mimetic combinations in lymphoma and in general for toxic drugs in cancer therapy.
- |||||||||| S63845 / Servier, Novartis, Ligand
Journal: Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML. (Pubmed Central) - Dec 16, 2021
BH3 profiling demonstrates their addiction to myeloid cell leukemia-1 (MCL1), which can be targeted with the small molecule inhibitor S63845...Combined MAPK and MCL1 inhibition restores apoptosis of CMML patient monocytes and reduces the expansion of patient-derived xenografts in mice. These results designate the combined inhibition of MCL1 and MAPK as a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, Ligand
Journal, IO biomarker: Stroma-Mediated Resistance to S63845 and Venetoclax through MCL-1 and BCL-2 Expression Changes Induced by miR-193b-3p and miR-21-5p Dysregulation in Multiple Myeloma. (Pubmed Central) - Nov 21, 2021
Additionally, direct contact with pMSCs under S63845 and/or venetoclax treatment modifies myeloma cell dependence on different BCL-2 family anti-apoptotic proteins in relation to BIM, making myeloma cells more dependent on the non-targeted anti-apoptotic protein or BCL-X. Finally, we show a potent effect of the combination of S63845 and venetoclax even in the presence of pMSCs, which supports this combinatorial approach for the treatment of MM.
- |||||||||| imatinib / Generic mfg.
Hereditary Chronic Neutrophilic Leukemia in a Four Generation Family without Transformation to Acute Leukemia (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_5283;
Prior therapies for the proband included imatinib, splenectomy, and hydroxyurea...Treatment with ruxolitinib resulted in improvement of her leukocyte count to 43.0 x 10 9 /L with 73% granulocytes, and reduction in her alkaline phosphatase from 732 IU/L to 296 IU/L...Notably, inhibition of MCL1 using S63845 reversed the anti-apoptotic effect induced by ligand-activation of the CSF3R receptor in PMNs (P < 0.001, Figure 1C)...Nonetheless, our observations highlight the need for germline testing of patients with CNL to better understand the natural history of CNL. Moreover, our data provide further insight into the pathobiology of CNL and potential novel targets for therapy.
- |||||||||| Targeting Bclxl Mitigates Mcl1 Chemoresistance in Multiple Myeloma (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_4296;
A combinatorial approach targeting Mcl1 and BclxL induced immediate and significant anti-MM effect both in vitro and ex vivo but proved to be toxic in vivo . Combination of the anti-MM therapeutic panobinostat in combination with S635845 recapitulated the anti-MM activity seen with A1331852 and warrants further evaluation.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, pelcitoclax (APG-1252) / Ascentage Pharma
Dual BCL-2/BCL-XL Inhibitor Pelcitoclax (APG-1252) Overcomes Intrinsic and Acquired Resistance to Venetoclax in Multiple Myeloma Cells (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_4295;
P1
In vivo study using pelcitoclax is ongoing and will be presented at the meeting. In conclusion, we report that venetoclax resistance in MM evolves from outgrowth of persister clones displaying activation of the ERK pathway and a shift in mitochondrial dependency towards BCL-xL, which can potentially be effectively targeted via the novel BCL-2/BCL-xL inhibitor pelcitoclax (APG-1252), which is currently in clinical investigation for solid tumors (NCT03080311).
- |||||||||| Nexavar (sorafenib) / Bayer, Amgen
Combination Therapy of FLT3 Tyrosine Kinase Inhibitors and BH3 Mimetics Targeting Antiapoptotic MCL-1 Synergistically Eliminates FLT3-ITD Acute Myeloid Leukemia Cells in Vitro and In Vivo (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_3866;
We have recently shown for the first time that a novel MCL-1 inhibitor S63845 elicited synergistic activity with FLT3 inhibitors AC220, sorafenib and with a multi-kinase inhibitor midostaurin at nanomolar doses in pre-clinical in vitro models of FLT3-ITD AML, including cells resistant to venetoclax ( Skwarska A, et al...Mice were treated for 3 weeks with low doses of midostaurin (25 mg/kg/5 days per week) and with MIK665, structurally optimized version of S63845 Mcl-1 inhibitor with improved pharmacokinetics in mice ( Halilovic E, et al...The long-term effect of combination on mice survival is currently being tested and will be reported. Altogether, our results indicate that efficacy of FLT3-ITD inhibitors can be enhanced through combination with low doses BH3 mimetics targeting MCL-1 and provide a rationale for the clinical evaluation of such combinations in FLT3 mutant AML patients.
- |||||||||| Targeting BCL-XL and BCL-2 By Protac 753B Effectively Eliminates AML Cells and Enhances Efficacy of Chemotherapy By Targeting Senescent Cells (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_3848;
We first evaluated the sensitivity of genetically diverse 17 leukemia cell lines, including 10 AML, 5 T-ALL and 2 MPN-AML to BCL-XL/BCL-2 dual inhibitor ABT263, 1 st generation BCL-XL PROTAC DT2216 ( Khan et al., Nature Medicine 2019 ) and BCL-XL/BCL-2 PROTAC 753B...We found that Ara-C indeed induced cellular senescence (SnCs) in MOLM-14 and Kasumi-1 AML cells, as manifested by increased cell size, induction of senescence-associated β-galactosidase activity (Fig...753B induced 50% cell killing at concentration of 1.3 μM, and nearly complete cell killing when combined with 5nM S63845 in OCI-AML2 at 24hr (Fig.1H), suggesting a synergistic effect in inducing apoptosis...753B showed potency comparable to ABT-263 in 15 AML samples, including 9 Venetoclax-resistant samples defined as IC50>1 μM (median IC 50 , 753B - 0.197 μM; ABT-263 - 0.280 μM) (Fig...In summary, BCL-XL/BCL-2 PROTAC 753B potently reduced cell viability through induction of apoptosis, and eliminated chemotherapy-induced senescent leukemia cells. In vivo efficacy studies of 753B combined with chemotherapy in the cell line- and patient-derived xenografts are ongoing and will be updated.
- |||||||||| sepantronium bromide (YM155) / Astellas, S63845 / Servier, Novartis, Ligand, Rituxan (rituximab) / Biogen, Zenyaku Kogyo, Roche
In silico Prediction Followed By In Vitro validation Identifies a Survivin Inhibitor and an MCL-1 Inhibitor As a Potent Secondary Drug Against Refractory or Relapsed Mantle Cell Lymphoma (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_2750;
Combination therapies such as R-CHOP, R-DHAP, Hyper-CVAD, VcR-CAP constitute the front-line chemotherapeutic treatment landscape for MCL...Our results showed that the YM155 and S63845 exhibited significant synergistic cell killing activities (Combination index/ CI value of 0.31±0.49 as calculated using Chou-Talalay's CI theorem, C.I>1 depicts synergism) alone and in combination with Bortezomib (PI) and Ibrutinib (BTKi), especially in R/R MCL cell lines...As both YM155 and S63845 have reported activity against cancer stem-ness, we will further investigate the effect of our novel drugs on the cancer stem-like cells in MCL, which have a potential role in treatment resistance. The secDrug algorithm promises to serve as a universal prototype for the discovery of novel drug combination regimens for treatment outcomes in any cancer type by enhancing sensitivity or overcoming resistance to standard of care drugs.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, Ligand, A-1331852 / AbbVie
Synergistic Activity of BH3-Mimetics By Combined Targeting of Anti-Apoptotic Regulators in B-Cell Precursor ALL (GWCC - B302-B303, Level 3) - Nov 5, 2021 - Abstract #ASH2021ASH_2195;
Taken together, we found heterogeneous responses of BCP-ALL samples to BH3-mimetics antagonizing BCL-2, MCL-1 and BCL-XL. The ability of leukemia cells to adapt their anti-apoptotic dependency from BCL-2 to MCL-1 or BCL-XL can be used as target for combination therapy, demonstrating synergistic activity in PDX samples ex vivo and in vivo .
- |||||||||| ipatasertib (GDC-0068) / Roche, S63845 / Servier, Novartis, Ligand, A-1331852 / AbbVie
Journal: ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins. (Pubmed Central) - Oct 28, 2021
In addition, we identified the AKT inhibitor ipatasertib and two BH3 mimetics targeting these anti-apoptotic proteins, S63845 and A-1331852, as new potential therapies for this type of cancer. Therefore, we postulate the sequential inhibition of both proteins using BH3 mimetics as a new treatment option for refractory and relapsed ER+ breast cancer tumors.
- |||||||||| Farydak (panobinostat) / Novartis
[VIRTUAL] Targeting BclxL with panobinostat mitigates Mcl1 chemoresistance in Multiple Myeloma () - Oct 10, 2021 - Abstract #BLOOD2021BLOOD_4;
A combinatorial approach targeting Mcl1 and Bclxl induced immediate and significant anti-MM effect both in vitro and ex vivo but proved to be toxic in vivo. Combination of the antiMM therapeutic panobinostat in combination with S635845 recapitulated the anti-MM activity seen with A1331852 and warrants further evaluation.
- |||||||||| Mekinist (trametinib) / Novartis, S63845 / Servier, Novartis, Ligand, Sutent (sunitinib) / Pfizer
Journal, IO biomarker: MCL-1 Inhibition Overcomes Anti-apoptotic Adaptation to Targeted Therapies in B-Cell Precursor Acute Lymphoblastic Leukemia. (Pubmed Central) - Sep 28, 2021
We found that the MEK inhibitor trametinib and the multi-target tyrosine kinase inhibitor sunitinib exquisitely increased apoptotic priming in an NRAS-mutant and in a KMT2A-rearranged cell line presenting a high expression of FLT3, respectively...To overcome this adaptation, we employed the BH3 mimetic S63845, a specific MCL-1 inhibitor, and evaluated its sequential addition to both kinase inhibitors to overcome resistance...Similar observations were made in BCP-ALL KMT2A-rearranged PDX cells in response to sunitinib, showing an analogous DBP profile to the SEM cell line. These findings demonstrate that rational sequences of targeted agents with BH3 mimetics, now extensively explored in clinical trials, may improve treatment effectiveness by overcoming anti-apoptotic adaptations in BCP-ALL.
- |||||||||| [VIRTUAL] New Targetable Pathways in Chronic Lymphocytic Leukemia (CLL) () - Sep 6, 2021 - Abstract #SOHO2021SOHO_385;
P1/2
We and others reported that preclinical efficacy of AZ5576, a selective inhibitor of CDK9, and its clinical congener AZD4573 in lymphoid tumors depended on rapid downmodulation of MCL1, BFL1, and MYC.19–21 CDK9 inhibition can increase efficacy of BH3-mimetics, but safety of this combination will need to be explored.22,23 CDK9 inhibitors in development, in addition to AZD4573, include VIP152, CYC065, and voruciclib...Navitoclax is a small-molecule inhibitor of BCL2, BCLX, and BCL2L2; however, its use in CLL has been plagued by thrombocytopenia.24 AZD4320 is an alternative agent that co-targets BCL2/X...ABBV-155, an antibody-drug conjugate targeting BCLX, where BCLX is being used as a payload to avoid “off-tumor” effects, demonstrated promise in solid tumor models.26 Finally, as many microenvironment-driven pro-survival pathways converge on NFB, leading to induction of chemokines, cell cycle regulators, and BCL2 family proteins themselves, this transcription factor continues to be an attractive target in CLL...When combined with ibrutinib in murine CLL models, VAY-736 produced prolonged survival compared with either therapy alone.28 Alternative targets for therapeutic antibodies include ROR1 (cirmtuzumab), CD19 (tafasitamab), and others.29 As resistance to novel agents is becoming an unmet need in CLL, exploration of novel targets is of paramount importance...Multiple CDK inhibitors are currently being explored and have anti-tumor effects not restricted to MCL1 inhibition. CAR T cells and bi-specific antibodies have exceptional efficacy in lymphoid malignancies and thus are of high relevance in CLL.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie
Journal, IO biomarker: Pairing MCL-1 inhibition with venetoclax improves therapeutic efficiency of BH3-mimetics in AML. (Pubmed Central) - Jul 31, 2021
Our data suggest that co-dependency on Bcl-xL and Mcl-1 is common, and co-inhibition of these molecules appears is synergistic in most HNSCC cells. These results are therefore of great relevance for clinicians as they provide the rational for combining BCL-2 and MCL-1 inhibition in AML.
- |||||||||| S63845 / Servier, Novartis, Ligand
THERAPEUTIC EFFICACY OF THE MCL-1 INHIBITOR S63845 IN CHOLANGIOCARCINOMA () - Jul 25, 2021 - Abstract #AHPBA2021AHPBA_235;
MCL-1 is a downstream target of YAP and is an anti-apoptotic protein implicated in the evasion of cell death in numerous solid tumors including CCA, making it attractive for targeted therapy. In this study, we demonstrate increased MCL-1 copy number in select CCA PDXs.
- |||||||||| S63845 / Servier, Novartis, Ligand
Journal: Direct P70S6K1 inhibition to replace dexamethasone in synergistic combination with MCL-1 inhibition in multiple myeloma. (Pubmed Central) - Jun 28, 2021
Dexamethasone and the myeloid cell leukemia 1 (MCL-1) inhibitor S63845 (MCL-1i) proved the most potent combination in our lethality screen and induced apoptosis of human myeloma cell lines (HMCLs) that was 50% higher compared with an additive drug effect...Combined, our results show a strong rationale for combination treatments using the P70S6K inhibitor in MM. Direct and specific inhibition of P70S6K may also provide a solution for patients ineligible or insensitive to dexamethasone or other glucocorticoids.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, MIK665 / Novartis
Journal, IO biomarker: Unmasking BCL-2 Addiction in Synovial Sarcoma by Overcoming Low NOXA. (Pubmed Central) - Jun 3, 2021
P1
Importantly, the venetoclax/S63845 combination induced tumor regressions in SS patient-derived xenograft (PDX) models. As a very close analog of S63845 (S64315) is now in clinical trials with venetoclax in AML (NCT03672695), the combination of MCL-1 BH3 mimetics and venetoclax should be considered for SS patients as a new therapy.
- |||||||||| dexamethasone / Generic mfg.
Journal: Selective drug combination vulnerabilities in STAT3- and TP53-mutant malignant NK cells. (Pubmed Central) - Jun 1, 2021
However, 4 combinations were identified that selectively eradicated the cancer cells and did not allow for development of resistance: ruxolitinib combined with the mouse double-minute 2 homolog (MDM2) inhibitor idasanutlin in STAT3-mutant, TP53 wild-type cell lines; ruxolitinib combined with the farnesyltransferase inhibitor tipifarnib in TP53-mutant cell lines; and ruxolitinib combined with either the glucocorticoid dexamethasone or the myeloid cell leukemia-1 (MCL-1) inhibitor S63845 but both without a clear link to underlying genetic features. In conclusion, using a new drug sensitivity screening approach, we identified drug combinations that selectively target mature NK-cell neoplasms and do not allow for development of resistance, some of which can be applied in a genetically stratified manner.
- |||||||||| S63845 / Servier, Novartis, Ligand
[VIRTUAL] CD157/BST-1 mediates pro-survival signals in acute myeloid leukemia () - May 30, 2021 - Abstract #EACR2021EACR_883;
When used in combination with AraC, S63845 significantly increases the therapeutic efficacy of AraC in CD157-positive but not in CD157-negative AML cells, overcoming their baseline difference in AraC sensitivity. Conclusion CD157 has an important functional role in the biology of AML and it could be a promising candidate for the prospective identification of patients that could benefit from therapies exploiting Mcl-1 inhibition.
- |||||||||| S63845 / Servier, Novartis, Ligand
[VIRTUAL] CD157/BST-1 mediates pro-survival signals in acute myeloid leukemia () - May 30, 2021 - Abstract #EACR2021EACR_882;
When used in combination with AraC, S63845 significantly increases the therapeutic efficacy of AraC in CD157-positive but not in CD157-negative AML cells, overcoming their baseline difference in AraC sensitivity. Conclusion CD157 has an important functional role in the biology of AML and it could be a promising candidate for the prospective identification of patients that could benefit from therapies exploiting Mcl-1 inhibition.
- |||||||||| S63845 / Servier, Novartis, Ligand
[VIRTUAL] CD157/BST-1 mediates pro-survival signals in acute myeloid leukemia () - May 30, 2021 - Abstract #EACR2021EACR_881;
When used in combination with AraC, S63845 significantly increases the therapeutic efficacy of AraC in CD157-positive but not in CD157-negative AML cells, overcoming their baseline difference in AraC sensitivity. Conclusion CD157 has an important functional role in the biology of AML and it could be a promising candidate for the prospective identification of patients that could benefit from therapies exploiting Mcl-1 inhibition.
- |||||||||| S63845 / Servier, Novartis, Ligand
[VIRTUAL] CD157/BST-1 mediates pro-survival signals in acute myeloid leukemia () - May 30, 2021 - Abstract #EACR2021EACR_880;
When used in combination with AraC, S63845 significantly increases the therapeutic efficacy of AraC in CD157-positive but not in CD157-negative AML cells, overcoming their baseline difference in AraC sensitivity. Conclusion CD157 has an important functional role in the biology of AML and it could be a promising candidate for the prospective identification of patients that could benefit from therapies exploiting Mcl-1 inhibition.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, Ligand
Journal: Inhibition of the anti-apoptotic protein MCL-1 severely suppresses human hematopoiesis. (Pubmed Central) - May 28, 2021
To predict side effects of therapeutic MCL-1 inhibition on the human hematopoietic system, we used RNAi and the small molecule inhibitor S63845 on cord blood-derived CD34+ cells...In contrast, mature blood cells survived normally in the absence of MCL-1. Combined inhibition of MCL-1 and BCL-XL resulted in synergistic effects with relevant loss of colony-forming HSPCs already at inhibitor concentrations of 0.1 μM each, indicating "synthetic lethality" of the two BH3-mimetics in the hematopoietic system.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, Ligand, Bcl-2 Family Inhibitors / Novartis, Infinity Pharma
Journal, IO biomarker: Reduced Mitochondrial Apoptotic Priming Drives Resistance to BH3 Mimetics in Acute Myeloid Leukemia. (Pubmed Central) - May 27, 2021
BCL-2 inhibition drives sequestered pro-apoptotic proteins to MCL-1 and vice versa, explaining why in vivo combinations of BCL-2 and MCL-1 antagonists are more effective when concurrent rather than sequential. Finally, drug-induced mitochondrial priming measured by dynamic BH3 profiling (DBP) identifies drugs that are persistently active in BH3 mimetic-resistant myeloblasts, including FLT-3 inhibitors and SMAC mimetics.
- |||||||||| Journal: Cotargeting BCL-2 and MCL-1 in high-risk B-ALL. (Pubmed Central) - May 15, 2021
In PDX models, combined BCL-2 and MCL1 targeting eradicated ALL from Ph- and Ph+ B-ALL cases, although fatal tumor lysis was observed in some instances of high tumor burden. We conclude that a dual BH3-mimetic approach is highly effective in diverse models of high-risk human B-ALL and warrants assessment in clinical trials that incorporate tumor lysis precautions.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Zarzio (filgrastim biosimilar) / Novartis
[VIRTUAL] PH+ ALL CELL LINE WITH PTPN11 MUTATIONS IS RESISTANT TO ALL TKIS AS WELL AS VENETOCLAX BUT SENSITIVE TO THE COMBINATION () - May 13, 2021 - Abstract #EHA2021EHA_820;
Results In comparison to parental, the SUP-B15 IR, DR and PR cell lines were resistant to all TKIs (imatinib, nilotinib, dasatinib and ponatinib) and to asciminib...Whilst these cell lines were resistant to the Mcl-1‐selective inhibitor S63845 (LD50=290 nM vs 78.5 nM for parental), combination therapy with venetoclax was synergistic in overcoming resistance (CI=0.051 for 50 nM S63845 and 5 nM venetoclax)...The DRKRASmut and PRNRASmut lines instead showed overexpression of Bcl-2 (P=0.0079 and P=0.01 respectively), but not pBCR-ABL or Mcl-1, which could explain why venetoclax alone overcame resistance in these cell lines Conclusion Combination therapy of TKIs and venetoclax could be promising for Ph+ ALL patients carrying PTPN11 mutations and Mcl-1 overexpression. Studies are ongoing to determine the role of the mutations in PTPN11 in the development of the resistance.
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