ArticleLeukemia2019
Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia.
Article in Leukemia, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 102 papers.
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Who cites it
102 citing papers in PubMed, 172 citations in OpenAlex.
- Pitavastatin counteracts venetoclax resistance mechanisms includingBlood neoplasia · 2026Article
- The myeloid cell leukaemia-1 inhibitor MIK665 is a potent therapy in preclinical models of paediatric acute myeloid leukaemia.British journal of haematology · 2026Article
- Predictors of response and rational combinations for the novel MCL-1 inhibitor MIK665 in acute myeloid leukemia.Molecular oncology · 2026Article
- Article
- Triplet regimens for all: genomically agnostic approaches to improve on HMA + VEN in AML?Hematology. American Society of Hematology. Education Program · 2025Review
- Pitavastatin counteracts venetoclax resistance mechanisms in acute myeloid leukemia by depleting geranylgeranyl pyrophosphate.bioRxiv : the preprint server for biology · 2025Article
- Apoptosis-targeting BH3 mimetics: transforming treatment for patients with acute myeloid leukaemia.Nature reviews. Clinical oncology · 2025Review
- Understanding the Functional Dependence and Inhibition of the Bcl‑2 Pro-Survival Proteins in a Wide Spectrum of Cancers toward Precision Medicine.ACS pharmacology & translational science · 2025Article
- Re-appraising assays on permeabilized blood cancer cells testing venetoclax or other BH3 mimetic agents selectively targeting pro-survival BCL2 proteins.Cell death and differentiation · 2025Article
- NGF/BDNF-Trk/p75NTR signaling in osteosarcoma immunity: biomarkers and therapeutic opportunities.Frontiers in immunology · 2025Review
- The tubulin polymerization inhibitor gambogenic acid induces myelodysplastic syndrome cell apoptosis through upregulation of Fas expression mediated by the NF-κB signaling pathway.Cancer biology & therapy · 2024Article
- Calaspargase-Pegol-Mknl Combined with BCL-2 and MCL-1 Inhibition for Acute Myeloid Leukemia.International journal of molecular sciences · 2024Article
- Venetoclax triggers sublethal apoptotic signaling in venetoclax-resistant acute myeloid leukemia cells and induces vulnerability to PARP inhibition and azacitidine.Cell death & disease · 2024Article
- Blockage of BCL-XL overcomes venetoclax resistance across BCL2+ lymphoid malignancies irrespective of BIM status.Blood advances · 2024Article
- Combating Acute Myeloid Leukemia via Sphingosine Kinase 1 Inhibitor-Nanomedicine Combination Therapy with Cytarabine or Venetoclax.Pharmaceutics · 2024Article
- Inhibition of NRF2 enhances the acute myeloid leukemia cell death induced by venetoclax via the ferroptosis pathway.Cell death discovery · 2024Article
- Vitamin K2 sensitizes the efficacy of venetoclax in acute myeloid leukemia by targeting the NOXA-MCL-1 pathway.PloS one · 2024Article
- Current Advances and Future Strategies for BCL-2 Inhibitors: Potent Weapons against Cancers.Cancers · 2023Review
- Identification of bicyclic compounds that act as dual inhibitors of Bcl-2 and Mcl-1.Molecular diversity · 2023Article
- An Overview of Targeted Therapies in Acute Myeloid Leukemia.HemaSphere · 2023Review
42 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
27 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Improving outcomes in acute myeloid leukemia (AML) remains a major clinical challenge. Overexpression of pro-survival BCL-2 family members rendering transformed cells resistant to cytotoxic drugs is a common theme in cancer. Targeting BCL-2 with the BH3-mimetic venetoclax is active in AML when combined with low-dose chemotherapy or hypomethylating agents. We now report the pre-clinical anti-leukemic efficacy of a novel BCL-2 inhibitor S55746, which demonstrates synergistic pro-apoptotic activity in combination with the MCL1 inhibitor S63845. Activity of the combination was caspase and BAX/BAK dependent, superior to combination with standard cytotoxic AML drugs and active against a broad spectrum of poor risk genotypes, including primary samples from patients with chemoresistant AML. Co-targeting BCL-2 and MCL1 was more effective against leukemic, compared to normal hematopoietic progenitors, suggesting a therapeutic window of activity. Finally, S55746 combined with S63845 prolonged survival in xenograft models of AML and suppressed patient-derived leukemia but not normal hematopoietic cells in bone marrow of engrafted mice. In conclusion, a dual BH3-mimetic approach is feasible, highly synergistic, and active in diverse models of human AML. This approach has strong clinical potential to rapidly suppress leukemia, with reduced toxicity to normal hematopoietic precursors compared to chemotherapy.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.