Beyond the binding site: PROTAC-mediated protein degradation assists the therapeutic paradigm of hematological...

Hematological malignancies represent a growing global health burden, with conventional therapies limited by systemic toxicity and resistance mechanisms. Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that hijack cellular degradation machinery to eliminate, rather than merely inhibit, target proteins, enabling engagement of previously undruggable oncogenic drivers. This review synthesizes PROTAC applications across acute myeloid leukemia, lymphoid malignancies, and multiple myeloma, addressing targets including BRD4, FLT3, BCL-XL, BTK, and epigenetic regulators. Clinical advancement has been notable, with Bruton tyrosine kinase (BTK) degraders achieving response rates exceeding 75% in heavily pretreated patients and progressing to Phase 3 trials, while cereblon-targeting degraders in multiple myeloma represent the most clinically mature application. Mechanistically, PROTACs offer catalytic, substoichiometric activity, elimination of non-catalytic protein functions, and retention of efficacy against certain resistance mutations. Significant challenges persist, however, including poor drug-like properties, limited oral bioavailability, complex ternary-complex optimization, and degrader-specific resistance mechanisms such as E3 ligase loss or impaired proteasomal capacity, necessitating expanded biomarker surveillance frameworks. Emerging innovations, including degrader-antibody conjugates, novel E3 ligase recruiters, and artificial intelligence-driven design, aim to address these limitations. Integration with precision medicine and rational combination strategies positions targeted protein degradation as a potentially transformative approach for addressing longstanding unmet needs in blood cancer therapy, although substantial translational hurdles remain.