Handbook of experimental pharmacology最新文献

{"title":"Pharmacodynamics of Boronic Acids and Boronates.","authors":"Alina Barquet-Nieto, Eunice D Farfán-García, Ruth M Mayorga-López, Julia J Segura-Uribe, Bhaskar C Das, Marvin A Soriano-Ursúa","doi":"10.1007/164_2026_851","DOIUrl":"https://doi.org/10.1007/164_2026_851","url":null,"abstract":"<p><p>After 70 years of exploration in the synthesis and activity of boronic acids, synthetic boron-containing compounds (BBCs) have shown biological activity in vitro and in vivo, and some of them are currently used as drugs in humans.In this chapter, we describe the main advances in understanding the mechanisms of action of boronic acids and boronates. As the development of potential drugs in this category expands, some aspects are well understood from the current drugs. Moreover, the initial development of the marketed compounds is summarized and presented, along with the recent progress supporting their role as drugs. Additionally, the known and potential applications of these compounds in the treatment of human diseases are discussed.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SGLT2 Inhibitors as Potential Agents for Prevention, Treatment, and/or Improved Recovery from Acute Kidney Injury.","authors":"Dianet Sanchez-Vega, Ellen P Oskoui, Leah J Siskind","doi":"10.1007/164_2026_853","DOIUrl":"https://doi.org/10.1007/164_2026_853","url":null,"abstract":"<p><p>Acute kidney injury (AKI) results in rapid loss of blood filtration, reabsorption, and excretion of metabolic waste. AKI can progress to chronic kidney disease or even lead to premature death. AKI significantly worsens mortality in several of the top 20 leading causes of death as well as in populations of hospitalized patients postcoronary intervention or cardiac surgery or with sepsis. Experimental rodent models of AKI have been used to investigate the pathophysiology of the different AKI etiologies and their subtypes due to challenges of mechanistic studies and risks of acquiring kidney biopsies in human patients. The sodium-glucose cotransporter 2 (SGLT2), located on the apical membrane of early proximal tubules, is responsible for reabsorbing more than 90% of the filtered glucose back into the bloodstream. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduced AKI severity and/or improved recovery when tested in rodent models of AKI. While SGLT2i are not currently approved by the FDA to treat AKI, there is clinical evidence to support their use as preventative agents. Of note, most clinical evidence for the use of SGLT2 inhibitors for AKI comes from studies in which AKI was not the primary end point. Data obtained from retrospective studies and animal models of AKI provide rationale for randomized clinical trials on SGLT2 inhibitors to prevent or improve recovery from AKI.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Ubiquitin-Proteasome System: The Cell's Natural Destroyer.","authors":"Yingyue Zhang, Xu Li, Luyu Shi, Han Wang, Chuntong Li, Lu-Jun Liang","doi":"10.1007/164_2026_837","DOIUrl":"https://doi.org/10.1007/164_2026_837","url":null,"abstract":"<p><p>The ubiquitin-proteasome system (UPS) serves as the principal selective protein degradation machinery in eukaryotic cells, orchestrating proteostasis and regulating nearly all fundamental physiological processes. This chapter systematically delineates the UPS, tracing its discovery and dissecting its core molecular machinery. The hierarchical three-enzyme cascade directing ubiquitin tagging is described, with particular emphasis on the structural mechanisms governing ubiquitin activation and transfer. The architectural and functional organization of the 26S proteasome, which encompasses substrate recognition, deubiquitination, unfolding, and processive degradation, is comprehensively examined. In addition, the broad regulatory functions of the UPS are highlighted in the contexts of cell cycle progression, protein quality control, immune modulation, and apoptosis, and its pathological dysregulation in cancers and neurodegenerative disorders is underscored. Finally, the therapeutic landscape is surveyed, covering clinical proteasome inhibitors, agents targeting E1 and E2 enzymes, and emerging modalities such as PROTACs and molecular glues that harness E3 ligases for targeted protein degradation.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Physiology of SGLT2 Inhibitors in Non-diabetic and Diabetic Individuals.","authors":"Ele Ferrannini","doi":"10.1007/164_2026_824","DOIUrl":"https://doi.org/10.1007/164_2026_824","url":null,"abstract":"<p><p>Sodium-glucose cotransporter 2 (SGLT2) inhibitors were developed as glucose-lowering agents but have emerged as cardiorenal therapies in people with and without diabetes. Their primary pharmacological action is restricted to the proximal renal tubule, where inhibition of SGLT2 reduces glucose and sodium reabsorption and induces sustained glycosuria. This chapter examines the physiological cascade linking this renal effect to systemic metabolic, hemodynamic, and cardiorenal consequences. In both diabetic and non-diabetic individuals, SGLT2 inhibition lowers the renal threshold for glucose excretion, increases distal sodium delivery, and transiently promotes osmotic diuresis and natriuresis. Downstream SGLT1 partially compensates for reduced proximal glucose reabsorption, limiting urinary glucose losses despite SGLT2 blockade.The resulting fall in plasma glucose and insulin shifts substrate utilization from carbohydrate toward fatty acids and ketone bodies, while uricosuria lowers serum uric acid. Over longer periods, changes include modest reductions in plasma volume and blood pressure, mobilization of tissue sodium, increased hematocrit and hemoglobin, altered renal oxygenation, and an initial decline followed by slower long-term loss of glomerular filtration rate. These effects interact across renal, metabolic, and hemodynamic pathways. Glycosuria also creates a chronic negative energy balance, although compensatory hyperphagia limits the degree of weight loss. Secondary consequences include modulation of intrarenal hemodynamics, endogenous glucose production, circulating substrates, vascular function, oxygen delivery, and established cardiorenal risk factors. Evidence from physiological studies and large clinical trials supports glycosuria as the initiating event from which multiple downstream effects arise. No single mechanism fully explains the long-term cardiovascular and renal benefits of SGLT2 inhibition. Rather, repeated, substantial glycosuria appears to induce a coordinated transition to a distinct physiological state in which several individually modest renal, metabolic, and hemodynamic adaptations converge to produce cardiorenal protection. This integrated model may better explain why clinical benefits extend beyond glucose lowering and are observed across populations, including individuals without diabetes.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteolysis Targeting Chimeras (PROTACs): Design and Mechanism.","authors":"Xiajing Lin, Yan Zhang, Chenhui Wang","doi":"10.1007/164_2026_838","DOIUrl":"https://doi.org/10.1007/164_2026_838","url":null,"abstract":"<p><p>Proteolysis-targeting chimeras (PROTACs) are driving a fundamental shift in small-molecule drug discovery from the traditional \"occupation-driven\" to the innovative \"event-driven\" pharmacological paradigm. This chapter systematically reviews the development of PROTAC technology and provides a detailed analysis of the dynamic process by which it hijacks the ubiquitin-proteasome system (UPS) to mediate the catalytic degradation of the protein of interest (POI). It delves into the thermodynamic effects driving the formation of the \"POI-PROTAC-E3 ligase\" ternary complex, as well as the hook effect mechanism that determines the therapeutic window. Regarding the rational design and optimization of PROTACs, this chapter comprehensively discusses the development principles for three core modules. It systematically explains the modification rules and covalent strategies for the solvent-exposed regions of POI ligands. It then summarizes the applications of classical E3 ligases and focuses on the expansion of the toolkit of novel E3 ligases, including FEM1B, the RNF family, and DCAF16. In addition, it provides an in-depth analysis of the critical role played by the evolution of linkers, from traditional flexible or rigid structures toward macrocyclization, bioorthogonal self-assembly, and molecular hinges, in enhancing druggability. Combining the revolutionary application of artificial intelligence (AI) in ligand and linker design with the latest clinical translation milestones, this chapter provides comprehensive theoretical support and practical guidance for conquering \"undruggable\" targets, overcoming clinical drug resistance, and developing the next generation of highly effective PROTACs.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Evidence of Cardioprotective Effects of SGLT2 Inhibitors.","authors":"Muhammad Shariq Usman, Subodh Verma, Ambarish Pandey","doi":"10.1007/164_2026_827","DOIUrl":"https://doi.org/10.1007/164_2026_827","url":null,"abstract":"<p><p>Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as foundational therapies across the cardio-kidney-metabolic (CKM) syndrome. Initially developed as glucose-lowering agents for type 2 diabetes mellitus (T2DM), these medications demonstrated substantial cardiovascular and renal benefits in large cardiovascular outcomes trials, fundamentally changing the management of heart failure (HF), chronic kidney disease (CKD), and T2DM. Early landmark trials, including EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, and VERTIS CV, established reductions in hospitalization for heart failure (HHF) and favorable renal outcomes in patients with T2DM, with more selective effects on atherosclerotic cardiovascular disease outcomes. Subsequent dedicated HF trials demonstrated that SGLT2 inhibitors provide clinically meaningful benefit across the left ventricular ejection fraction spectrum. In patients with heart failure with reduced ejection fraction (HFrEF), DAPA-HF and EMPEROR-Reduced showed significant reductions in worsening HF and cardiovascular death regardless of diabetes status. Similar benefits were later demonstrated in heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF) in EMPEROR-Preserved and DELIVER, establishing SGLT2 inhibitors as among the first therapy classes to consistently reduce HF events across the HF spectrum. Dedicated CKD trials, including CREDENCE, DAPA-CKD, and EMPA-KIDNEY, further showed substantial slowing of kidney disease progression and reduction in cardiorenal outcomes, both in patients with and without T2DM. Despite robust evidence and incorporation into major international guidelines, uptake of these therapies in clinical practice remains suboptimal. Increased implementation of these therapies in routine clinical practice is essential to improve outcomes across the CKM spectrum.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-Throughput Screen for Candidate PROTAC Identification.","authors":"Xiaotong Chen, Cheng-Liang Zhu","doi":"10.1007/164_2026_841","DOIUrl":"https://doi.org/10.1007/164_2026_841","url":null,"abstract":"<p><p>The identification of potent and selective proteolysis targeting chimeras (PROTACs) presents unique screening challenges compared to traditional small-molecule inhibitor discovery, due to linker-dependent structure-activity relationships, ternary complex cooperativity, cellular permeability constraints, and the need to connect target engagement with productive ubiquitination and degradation. This chapter provides a methodological guide to the high-throughput screening (HTS) strategies for candidate PROTAC identification. We outline the workflow from the construction of focused chemical libraries to the implementation of orthogonal screening cascades. Key biochemical and biophysical approaches, including time-resolved fluorescence energy transfer (TR-FRET), AlphaLISA, fluorescence polarization (FP), surface plasmon resonance (SPR), and affinity selection-mass spectrometry (ASMS), are discussed for their utility in the rapid triage of PROTAC hits. We further discuss the role of cell-based assays, including NanoBRET, HiBiT, Cytoblot/in-cell immunodetection, high-throughput flow cytometry, and high-content imaging, which enable assessment of intracellular target engagement, degradation potency, selectivity, and mechanism of action. Emerging phenotypic, chemoproteomic, and computational strategies are also considered as complementary approaches for expanding the degradable target space and prioritizing high-quality candidates. Together, these screening modalities provide an integrated framework for accelerating the discovery and validation of PROTAC candidates.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PROTAC as a Potential Toolbox for the Discovery of New Targets and Drugs.","authors":"Mengjun Ma, Xiaolei Meng, Chong Qin","doi":"10.1007/164_2026_839","DOIUrl":"https://doi.org/10.1007/164_2026_839","url":null,"abstract":"<p><p>With its event-driven degradation mechanism, proteolysis targeting chimera (PROTAC) is emerging as a powerful toolbox for novel drug discovery and target identification. In drug discovery, PROTAC enables the targeting of traditionally undruggable proteins, disrupts protein scaffolding functions, overcomes clinical drug resistance, and enhances target selectivity. In target identification, derivatizing bioactive molecules into PROTAC probes combined with proteomics permits precise identification of drug targets; furthermore, target-agnostic PROTAC libraries and tag-based degradation systems facilitate the de novo discovery and functional validation of unknown targets. PROTAC technology has evolved from a mere intervention tool to an integrated platform for new target and drug discovery, providing transformative strategies for precision medicine and innovative drug development.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Techniques for Accelerating the Understanding of PROTAC-Based Ternary Complex.","authors":"Ihsan Ullah, Jinghao Gao, Youyong Yuan","doi":"10.1007/164_2026_840","DOIUrl":"https://doi.org/10.1007/164_2026_840","url":null,"abstract":"<p><p>Proteolysis-targeting chimeras (PROTACs) are bifunctional small molecules capable of selectively degrading proteins by forming tertiary complexes with proteins of interest (POIs), E3 ubiquitin ligases, and degraders. Unlike traditional occupancy-driven inhibitors, PROTACs function through an event-driven mechanism, based on the thermodynamic, kinetic, and structural properties of the ternary complex assembly. This chapter provides an overview of the mechanistic and current knowledge of the ternary complexes formed by PROTAC and provides a review of the experimental and computational approaches applied to characterize them. Special emphasis is given to the role of cooperativity, residence time, conformational heterogeneity, and the interaction between ternary complex stability and productive ubiquitination. The structural, biophysical, cellular, proteomic, and computational approaches are presented with respect to their advantages and disadvantages. The representative case studies illustrate the role of the mechanistic insight in degrader design. A ternary complex-based and integrative framework is suggested to be used as the basis for the rational development of specific protein degraders.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding the E3 Ligase Landscape: From Small Molecule to Biological Targeted Protein Degradation.","authors":"Xuan Zhao, Yuhan Liu, Xucong Teng","doi":"10.1007/164_2026_842","DOIUrl":"https://doi.org/10.1007/164_2026_842","url":null,"abstract":"<p><p>Targeted protein degradation (TPD), particularly proteolysis-targeting chimeras (PROTACs), has emerged as a powerful strategy for eliminating disease-associated proteins through the ubiquitin-proteasome system. However, current PROTACs rely heavily on a limited number of E3 ligases, mainly CRBN and VHL, due to the scarcity of suitable ligands. This review summarizes the development of classical small-molecule E3 ligase ligands and highlights emerging biological recruitment strategies involving antibodies, nanobodies, aptamers, peptides, and engineered proteins. These approaches expand the accessible E3 ligase landscape, broaden the range of targetable proteins, and provide greater programmability and selectivity. Recent advances in delivery systems, modular activation, and artificial intelligence-assisted design are also discussed. Finally, keytranslational challenges, including intracellular delivery, immunogenicity, pharmacokinetics, manufacturing scalability, and off-target effects, are considered. Together, these advances provide a broader framework for developing more precise and versatile next-generation targeted protein degradation platforms.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}