Targeted degradation of protein in hematologic malignancies: mechanisms, therapeutic strategies, and clinical prospects.

Hematological malignancies, including leukemia, lymphoma, and multiple myeloma, remain a major cause of illness and death worldwide. Although treatment options such as targeted therapies and immunotherapies have improved survival and clinical outcomes, many tumors still develop resistance due to persistent oncogenic signaling and the inability of most small-molecule therapies to effectively target these proteins. Recently, targeted protein degradation has emerged as a new therapeutic approach that selectively degrades pathogenic proteins instead of only blocking their function. This approach uses cellular degradation mechanisms, especially the ubiquitin-proteasome system, to induce ubiquitination and proteasomal degradation of target proteins. PROTACs and molecular glue degraders are emerging strategies for selectively removing cancer-promoting proteins in hematologic malignancies. These approaches make it possible to target key regulators such as BCR-ABL, BTK, and BRD4, which are involved in leukemogenesis, lymphoma progression, and treatment resistance. Moreover, emerging degradation strategies such as LYTACs and AUTACs further expand the range of proteins that can be targeted. This review discusses the molecular mechanisms of targeted protein degradation and its therapeutic potential in hematologic malignancies. We summarize recent advances in degradation technologies, highlight key targets in leukemia, lymphoma, and multiple myeloma, and discuss current clinical developments across both preclinical and clinical studies.