ABSTRACT Extracellular targeted protein degradation (eTPD) has emerged as a new strategy for regulating the abundance and activity of extracellular and membrane proteins, with prominent potential to address traditionally undruggable targets in oncology, autoimmune diseases, and neurodegenerative disorders. Most eTPD platforms employ heterobifunctional chimeras that link proteins of interest (POIs) to specific endocytic effectors (EEs), either lysosome‐targeting receptors (LTRs) or membrane‐bound E3 ubiquitin ligases, to direct POIs to lysosomes for degradation. Since EE engagement dictates cellular uptake, intracellular trafficking route, recycling kinetics, tissue specificity, and overall degradation efficacy, one compelling topic in the eTPD community is to identify effective EEs for developing new eTPD tools. To inform new EE discovery, here we review the current landscape of EEs utilized in eTPD. We categorize LTRs based on their ligand specificity and discuss representative receptors including the cation‐independent mannose‐6‐phosphate receptor (CI‐M6PR) and the asialoglycoprotein receptor (ASGPR), with emphasis on their internalization and trafficking characteristics. For each category, we highlight representative degrader designs and assess how degrader attributes such as ligand format, valency, molecular size, linker chemistry, and linker length influence trafficking properties and degradation efficacy. We further discuss cell‐surface E3 ligase‐based degraders and emerging EE‐independent strategies—receptor‐independent membrane‐interacting modalities exemplified by cell‐penetrating peptides—that exploit alternative endocytic pathways without relying on specific effector expression. Finally, we discuss key challenges and future opportunities for integrating effector biology with degrader engineering to advance eTPD toward therapeutic drug discovery.
ABSTRACT Acute myeloid leukemia (AML) is the most common form of acute leukemia. It is characterized by unfavorable prognosis, elevated rates of recurrence, short overall survival and high mortality rates. Genetic and epigenetic aberrations contribute to its initiation and progression, presenting a considerable clinical challenge. Genomic investigations revealed that FMS‐like tyrosine kinase 3 (FLT3), a receptor tyrosine kinase regulating the proliferation and differentiation of hematopoietic cells, is overexpressed in AML leukemic blasts. To date, FDA has approved only three FLT3 inhibitors for targeted AML therapy (midostaurin, gilteritinib, quizartinib). These molecules feature several nitrogen atoms; in particular quizartinib contains an oxazole and a urea group that are involved in interactions with FLT3 kinase domain. Similarly, different N‐containing heterocycles have proven to play a key role in other FLT3 inhibitors. Though small‐molecule FLT3 inhibitors encompass various chemical classes, N‐containing heterocycles and particularly the azole core represent the most common scaffold. The electron‐rich properties of the azoles allow them to easily bind with enzymes and receptors. Based on this, we will provide a general overview of FLT3 inhibitor classes in AML, along with a comprehensive report on azole‐based structures, reviewing recent contributions to the field.
ABSTRACT Type 2 diabetes mellitus (T2DM) is a highly prevalent chronic metabolic disease worldwide, and the clinical prevention and control situation is severe. Although the various antidiabetic drugs currently in clinical use can lower blood glucose levels through different mechanisms, there are significant differences in efficacy among individuals. Existing evidence suggests that differences in gut microbiota (GM) composition and metabolic function may be one of the key factors contributing to the heterogeneity in drug efficacy. Based on this, this review describes the physiological and pathological mechanisms of the GM‐metabolism axis and systematically reviews the modulatory effects of different classes of antidiabetic drugs on this axis and their underlying mechanisms. Available studies suggest that metformin, α‐glucosidase inhibitors, dipeptidyl peptidase‐4 inhibitors (DPP‐4i), sodium‐glucose cotransporter‐2 inhibitors (SGLT2i), thiazolidinediones (TZDs), and oral glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) may differentially affect GM composition and/or microbial metabolites, including short‐chain fatty acids (SCFAs), branched‐chain amino acids (BCAAs), and bile acids. These alterations may be associated with glucose homeostasis and insulin resistance through pathways involving GPR41/43, HDACs, AMPK, mTORC1/S6K1, FXR‐FGF15/19, and TGR5‐GLP‐1 signaling. By integrating clinical and mechanistic evidence, this review highlights the potential contribution of the GM‐metabolism axis to the glucose‐lowering effects of antidiabetic drugs. However, the quantity and confidence of evidence vary substantially across drug classes, and causal and clinical relevance requires further validation. These findings provide a basis for future research on personalized interventions for T2DM characterized by SCFA‐producing bacterial deficiency, BCAA overload, or dysregulated bile acid metabolism.
ABSTRACT The five pore‐forming gasdermins (GSDMs, namely GSDMA‐E) are best known for executing pyroptosis, a lytic and highly inflammatory form of programmed cell death. Accumulating evidence over the past decade has unveiled diverse nonlytic functions of GSDMs in digestive homeostasis and disease. GSDMs preserve intestinal barrier integrity and mucosal immunity under physiological conditions, whereas their dysregulated activation fuels tissue injury across a spectrum of digestive diseases, including inflammatory bowel disease, acute intestinal injury, radiation enteritis, acute pancreatitis, and liver disorders. Notably, the functional outcome of GSDM activation is highly context‐dependent: the same protein can be either protective or injurious. This duality extends to digestive oncology, where GSDM‐mediated pyroptosis can stimulate or suppress antitumor immunity. GSDM‐targeted drugs, including GSDMD agonists, GSDMD inhibitors, and GSDME inhibitors, have shown encouraging efficacy in preclinical models, although none have yet reached the clinic. Here, we review the dual roles of GSDMs across the digestive system, outline the mechanistic basis of their form‐, cell‐, and tissue‐specific functions, and discuss the progress and remaining challenges in GSDM‐targeted therapy.
ABSTRACT Targeted elimination of pathogenic proteins remains a fundamental challenge in therapeutic intervention, particularly for proteins considered “undruggable” by conventional inhibition‐based approaches. Aptamer–based targeted protein degradation (TPD) has emerged as a versatile strategy that leverages the high specificity, structural programmability, and chemical tunability of nucleic acid aptamers to redirect disease‐relevant proteins toward endogenous degradation pathways. Intracellular platforms, exemplified by aptamer‐conjugated proteolysis‐targeting chimeras (PROTACs), induce ubiquitination and proteasomal degradation of cytosolic and nuclear targets. In parallel, extracellular and membrane‐targeting modalities, including aptamer‐conjugated lysosome‐targeting chimeras (LYTACs) and related lysosomal degradation systems, enable clearance of secreted and membrane‐bound proteins that are inaccessible to proteasome‐based strategies. Collectively, these approaches broaden the potentially degradable proteome and offer opportunities to improve target selectivity and therapeutic safety. However, most aptamer‐based TPD systems remain at the proof‐of‐concept or early preclinical stage, with limited standardization of degradation potency, kinetics, selectivity, and in vivo efficacy. Additional challenges include the discovery of functionally active aptamers, preservation of affinity and activity after chemical modification or conjugation, efficient delivery, chemical stability, controlled biodistribution, and mitigation of innate immune activation. This review provides a mechanistic and comparative framework for intracellular and extracellular aptamer‐based TPD strategies, with emphasis on quantitative performance, delivery considerations, technical bottlenecks, and their translational potential for precision protein‐targeted therapeutics.
