Targeted Protein Degradation in Acute Myeloid Leukemia: Emerging Role of PROTACs in Hematologic Malignancies

Acute myeloid leukemia (AML), a hematologic malignancy characterized by poor prognosis, frequent relapse, and resistance to standard therapies, remains challenging to treat. Recent advances in targeted therapy have offered limited success because of the incomplete eradication of leukemic stem cells and the emergence of drug resistance. Proteolysis-targeting chimeras (PROTACs) represent a novel therapeutic paradigm that facilitates the selective degradation of oncogenic proteins through the recruitment of E3 ubiquitin ligases. Unlike traditional inhibitors, PROTACs operate via an event-driven mechanism, enabling catalytic and often more durable suppression of disease-driving proteins. This review explores the mechanistic foundation of PROTACs and highlights their application against key molecular targets in AML, including BRD4, FLT3, CDK9, BCL-xL, and MLL fusion co-factors. Preclinical data demonstrate that PROTACs not only enhance therapeutic efficacy but also overcome the limitations of conventional inhibitors. Challenges such as pharmacokinetic limitations, tissue specificity, off-target effects, and manufacturing complexity are discussed alongside emerging strategies such as dual degraders, conditional activation, and biomarker-guided precision therapy. With ongoing advances, PROTACs hold substantial promise as next-generation agents capable of transforming AML treatment, particularly for relapsed and refractory cases.