Joshua ML Casan, John F. Seymour

Degraders Upgraded: The Rise of PROTACs in Haematological Malignancies

  • Cell Biology
  • Hematology
  • Immunology
  • Biochemistry

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 targets 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 (UPS), 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 sub-stoichiometric dosing that does not require an active or allosteric target binding site. Preliminary clinical data demonstrate promising therapeutic activity in heavily pre-treated populations and novel technology platforms are poised to exploit myriad 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 pre-clinical 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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