Apoptosis-targeting BH3 mimetics: transforming treatment for patients with acute myeloid leukaemia

Antonino Glaviano¹, Ellen Weisberg^{2

3}, Hiu Y Lam^{4

5}, Donavan J J Tan^{4

5

6}, Andrew J Innes^{7

8}, Yubin Ge⁹, Catherine E Lai¹⁰, Wendy Stock¹¹, Christina Glytsou^{12

13}, Linda Smit¹⁴, Tatsushi Yoshida¹⁵, Tian Y Zhang¹⁶, Vanessa E Kennedy¹⁷, B Douglas Smith¹⁸, Thomas Mercher¹⁹, Stéphane de Botton²⁰, Patrizia Diana¹, Marina Konopleva²¹, Michael J Mauro²², James D Griffin^{2

3}, Courtney D DiNardo²³, Alan P Kumar^{24

25}

Affiliations

¹ Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
³ Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁴ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁵ NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁶ School of Chemical and Life Sciences, Singapore Polytechnic, Singapore Polytechnic, Singapore, Singapore.
⁷ Centre for Haematology, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK.
⁸ Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.
⁹ Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
¹⁰ Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹¹ Department of Hematology and Oncology, Medical Center, University of Chicago, Chicago, IL, USA.
¹² Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
¹³ Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers University, The State University of New Jersey, New Brunswick, NJ, USA.
¹⁴ Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, VU Medical Center, Amsterdam, Netherlands.
¹⁵ Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
¹⁶ Department of Medicine, Division of Hematology, Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
¹⁷ Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University, Stanford, CA, USA.
¹⁸ Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
¹⁹ OPALE Carnot Institute, Gustave Roussy Cancer Campus, Université Paris-Saclay, Paris, France.
²⁰ Department of Hematology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Paris, France.
²¹ Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York City, NY, USA.
²² Myeloproliferative Neoplasms Program, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
²³ Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. cdinardo@mdanderson.org.
²⁴ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. apkumar@nus.edu.sg.
²⁵ NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. apkumar@nus.edu.sg.

PMID: 40890352
DOI: 10.1038/s41571-025-01068-0

Review

Apoptosis-targeting BH3 mimetics: transforming treatment for patients with acute myeloid leukaemia

Antonino Glaviano et al. Nat Rev Clin Oncol. 2025.

. 2025 Sep 1.

doi: 10.1038/s41571-025-01068-0. Online ahead of print.

Authors

Affiliations

¹ Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
³ Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁴ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁵ NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁶ School of Chemical and Life Sciences, Singapore Polytechnic, Singapore Polytechnic, Singapore, Singapore.
⁷ Centre for Haematology, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK.
⁸ Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.
⁹ Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
¹⁰ Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹¹ Department of Hematology and Oncology, Medical Center, University of Chicago, Chicago, IL, USA.
¹² Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
¹³ Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers University, The State University of New Jersey, New Brunswick, NJ, USA.
¹⁴ Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, VU Medical Center, Amsterdam, Netherlands.
¹⁵ Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
¹⁶ Department of Medicine, Division of Hematology, Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
¹⁷ Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University, Stanford, CA, USA.
¹⁸ Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
¹⁹ OPALE Carnot Institute, Gustave Roussy Cancer Campus, Université Paris-Saclay, Paris, France.
²⁰ Department of Hematology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Paris, France.
²¹ Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York City, NY, USA.
²² Myeloproliferative Neoplasms Program, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
²³ Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. cdinardo@mdanderson.org.
²⁴ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. apkumar@nus.edu.sg.
²⁵ NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. apkumar@nus.edu.sg.

PMID: 40890352
DOI: 10.1038/s41571-025-01068-0

Abstract

Acute myeloid leukaemia (AML) remains a challenging haematological malignancy, with most patients developing resistance to standard-of-care (SOC) treatments. This resistance is often attributed to the overexpression of anti-apoptotic BCL-2 family proteins, which regulate the intrinsic apoptotic pathway by inhibiting pro-apoptotic effector proteins such as BAX and BAK. AML cells exploit this imbalance to evade apoptosis and sustain survival, necessitating the development of novel therapeutic strategies. BH3 mimetics are small-molecule inhibitors targeting the pro-survival BCL-2 family proteins and have emerged as promising agents in patients with AML who are unable to receive high-intensity induction chemotherapy. Co-treatment with the BCL-2-specific inhibitor venetoclax and various SOC therapies has been proven effective, with several combinations now approved by the US Food and Drug Administration for adults with AML who are ≥75 years of age and/or are ineligible for intensive induction chemotherapy, on the basis of improved response rates and survival outcomes compared with the previous SOC. In this Review, we highlight the transformative potential of BH3 mimetics in AML therapy, including ongoing studies investigating novel combination regimens and efforts to further refine treatment strategies, with the ultimate goal of improving outcomes for patients with AML.

PubMed Disclaimer

Conflict of interest statement

Competing interests: B.D.S. is a consultant and adviser of Servier. M.K. is a consultant of AbbVie, Adaptive, AmMax, Curis, Janssen, Kyowa Kirin, Menarini/Stemline Therapeutics, Novartis, Sanofi Aventis, Servier and Vincerx and is an adviser of AbbVie, Auxenion GmbH, Dark Blue Therapeutics, Legend, MEI Pharma, Menarini/Stemline Therapeutics, Novartis and Syndax and receives research funding from AbbVie, Janssen and Klondike Biopharma. C.D.D. is a consultant and/or adviser of Abbvie, Astellas, AstraZeneca, BMS, Daiichi Sankyo, GenMab, GSK, Rigel, Ryvu, Schrodinger, Servier and Solu Therapeutics and has received research funding from Abbvie, Astex, Beigene, BMS, Jazz, ImmuneOnc, Remix, Servier, Schrodinger and Systimmune. A.P.K. serves on the advisory board for AUM Biosciences. The other authors declare no competing interests.

References

1. Melino, G. The Sirens’ song. Nature 412, 23 (2001). - PubMed
1. Kroemer, G. et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 16, 3–11 (2009). - PubMed
1. Cotter, T. G. Apoptosis and cancer: the genesis of a research field. Nat. Rev. Cancer 9, 501–507 (2009). - PubMed
1. Vitale, I. et al. Apoptotic cell death in disease-current understanding of the NCCD 2023. Cell Death Differ. 30, 1097–1154 (2023). - PubMed - PMC
1. Kayagaki, N., Webster, J. D. & Newton, K. Control of cell death in health and disease. Annu. Rev. Pathol. 19, 157–180 (2024). - PubMed

Publication types

Actions

LinkOut - more resources

Full Text Sources
- Nature Publishing Group
Research Materials
- NCI CPTC Antibody Characterization Program

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Apoptosis-targeting BH3 mimetics: transforming treatment for patients with acute myeloid leukaemia

Affiliations

Apoptosis-targeting BH3 mimetics: transforming treatment for patients with acute myeloid leukaemia

Authors

Affiliations

Abstract

Conflict of interest statement

Similar articles

References

Publication types

LinkOut - more resources

Full Text Sources

Research Materials