Targeted protein degradation (TPD) is a revolutionary approach to targeted therapy in hematological malignancies that potentially circumvents many constraints of existing small-molecule inhibitors. Heterobifunctional proteolysis-targeting chimeras (PROTACs) are the leading TPD drug class, with numerous agents now in clinical trials for a range of blood cancers. PROTACs harness the cell-intrinsic protein recycling infrastructure, the ubiquitin-proteasome system, to completely degrade target proteins. Distinct from targeted small-molecule inhibitor therapies, PROTACs can eliminate critical but conventionally “undruggable” targets, overcome resistance mechanisms to small-molecule therapies, and can improve tissue specificity and off-target toxicity. Orally bioavailable, PROTACs are not dependent on the occupancy-driven pharmacology inherent to inhibitory therapeutics, facilitating substoichiometric dosing that does not require an active or allosteric target binding site. Preliminary clinical data demonstrate promising therapeutic activity in heavily pretreated populations and novel technology platforms are poised to exploit a myriad of permutations of PROTAC molecular design to enhance efficacy and targeting specificity. As the field rapidly progresses and various non-PROTAC TPD drug candidates emerge, this review explores the scientific and preclinical foundations of PROTACs and presents them within common clinical contexts. Additionally, we examine the latest findings from ongoing active PROTAC clinical trials.
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REVIEW ARTICLE|
March 28, 2024
Degraders upgraded: the rise of PROTACs in hematological malignancies
Clinical Trials & Observations
Joshua M. L. Casan,
Joshua M. L. Casan
1Department of Clinical Haematology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
2Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
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John F. Seymour
John F. Seymour
1Department of Clinical Haematology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
2Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
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Blood (2024) 143 (13): 1218–1230.
Article history
Submitted:
November 20, 2023
Accepted:
December 19, 2023
First Edition:
January 3, 2024
Citation
Joshua M. L. Casan, John F. Seymour; Degraders upgraded: the rise of PROTACs in hematological malignancies. Blood 2024; 143 (13): 1218–1230. doi: https://doi.org/10.1182/blood.2023022993
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March 28 2024
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