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CHRONIC MYELOGENOUS LEUKEMIA

BCR::ABL1 Proteolysis-targeting chimeras (PROTACs): The new frontier in the treatment of Ph+ leukemias?

Leukemia volume 38, pages 1885–1893 (2024)Cite this article

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Abstract

BCR::ABL1 tyrosine kinase inhibitors (TKIs) have turned chronic myeloid leukemia (CML) from a lethal condition into a chronic ailment. With optimal management, the survival of CML patients diagnosed in the chronic phase is approaching that of age-matched controls. However, only one-third of patients can discontinue TKIs and enter a state of functional cure termed treatment-free remission (TFR), while the remainder require life-long TKI therapy to avoid the recurrence of active leukemia. Approximately 10% of patients exhibit primary or acquired TKI resistance and eventually progress to the blast phase. It is thought that recurrence after attempted TFR originates from CML stem cells (LSCs) surviving despite continued suppression of BCR::ABL1 kinase. Although kinase activity is indispensable for induction of overt CML, kinase-independent scaffold functions of BCR::ABL1 are known to contribute to leukemogenesis, raising the intriguing but as yet hypothetical possibility, that degradation of BCR::ABL1 protein may accomplish what TKIs fail to achieve – eliminate residual LSCs to turn functional into real cures. The advent of BCR::ABL1 proteolysis targeting chimeras (PROTACs), heterobifunctional molecules linking a TKI-based warhead to an E3 ligase recruiter, has moved clinical protein degradation into the realm of the possible. Here we examine the molecular rationale as well as pros and cons of degrading BCR::ABL1 protein. We review reported BCR::ABL1 PROTACs, point out limitations of available data and compounds and suggest directions for future research. Ultimately, clinical testing of a potent and specific BCR::ABL1 degrader will be required to determine the efficacy and tolerability of this approach.

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Fig. 1: Cellular mechanisms impacted by BCR::ABL1 scaffold functions.
Fig. 2: Signaling from BCR::ABL1 pY177 in the presence and absence of active BCR::ABL1 kinase.
Fig. 3: Schematic of proteolysis targeting chimeras (PROTACs).

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Acknowledgements

MWD was supported in part by R01CA268496, R01CA257602, and R01CA254354. WT was supported in part by NIH R35GM148266 and NIH R01CA284689. NCR is a Special Fellow of the Leukemia and Lymphoma Society.

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  1. Versiti Blood Research Institute, Milwaukee, WI, USA

    Nataly Cruz-Rodriguez, Benjamin Bateman & Michael Deininger

  2. Lachman Institute of Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA

    Hua Tang & Weiping Tang

  3. Department of Chemistry, University of Wisconsin-Madison, Madison, WI, USA

    Weiping Tang

  4. Medical College of Wisconsin, Milwaukee, WI, USA

    Michael Deininger

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NCR, HT, BB, WT and MWD wrote the manuscript and designed figures and tables. All authors read and edited the manuscript and approved of the final draft.

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Michael Deininger is a consultant for Blueprint Medicines, Novartis, CTIBioPharma, Incyte, Dava Oncology, Pfizer, and Cogent. Weiping Tang is a cofounder and shareholder of Chimergen Therapeutics Inc.

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Cruz-Rodriguez, N., Tang, H., Bateman, B. et al. BCR::ABL1 Proteolysis-targeting chimeras (PROTACs): The new frontier in the treatment of Ph+ leukemias?. Leukemia 38, 1885–1893 (2024). https://doi.org/10.1038/s41375-024-02365-w

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