Targeting APL fusion proteins by peptide interference.
A significant barrier to experimental therapeutics is the ability to identify and specifically target oncogenic proteins involved in the molecular pathogenesis of disease. In acute promyelocytic leukemia (APL), aberrant transcription factors and their associated machinery play a central role in mediating the malignant phenotype. The mechanism of action of APL chimeric fusion proteins involves their ability to either self-associate or interact with different partner proteins. Thus, targeting protein-protein interactions could have a significant impact in blocking the activity of APL oncoproteins. As therapeutic targets, the interface between interacting proteins may not always be amenable to highly specific small molecule blockade. In contrast, peptides are well-suited to this purpose and can be reliably delivered when fused to cell-permeable peptide domains. Therapeutic peptides can be designed to directly target APL fusion proteins, their downstream effectors, or other potentially synergistic oncogenic mechanisms of importance in APL blasts. In addition to serving as potential therapeutic agents, such reagents could serve as powerful reagents to dissect the molecular pathogenesis of APL.
Melnick
A
A
Department of Developmental and Molecular Biology and Medical Oncology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA. amelnick@aecom.yu.edu
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D021381:Protein Transport / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D015514:Oncogene Proteins, Fusion; D010455:Peptides; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein