Handbook of experimental pharmacology最新文献

{"title":"Mechanistic In Vitro Transporter Modelling: A Path to Consistent Intrinsic Kinetic Inputs Suitable for IVIVE of Transporters.","authors":"Matthew D Harwood, Mailys De Sousa Mendes, Sibylle Neuhoff","doi":"10.1007/164_2026_856","DOIUrl":"https://doi.org/10.1007/164_2026_856","url":null,"abstract":"<p><p>A key aspect of in vitro-to-in vivo extrapolation (IVIVE) linked to physiologically based pharmacokinetic (PBPK) modelling (IVIVE-PBPK) is ensuring that input data derived from in vitro assays intrinsically reflect the compound's true properties, free from the confounding effects of assay design, model structure, or data transformation methods. Having assurance in the model inputs provides an increased confidence in interpreting the model outcomes. Deriving the kinetics of transporter protein activity from in vitro experiments is complex, and the analytical approach applied to the experimental flux data requires careful consideration. Applying different data analysis approaches to the same dataset can yield markedly variable drug parameter estimates illustrating how readily these confounding factors bias the derived values. Mechanistic modelling of the in vitro data addresses this by integrating assay design, structural experimental system components, and statistical fitting to derive intrinsic, physiologically relevant drug parameter estimates that conventional analysis approaches often cannot achieve; this approach typically yields higher, less variable passive permeability estimates and lower, less variable K_i and K_m values. This chapter outlines in vitro assay designs for determining 'intrinsic' drug permeation and active transport kinetics, contrasts the challenges of conventional analysis approaches with the benefits of mechanistic modelling, and provides examples of where the mechanistic approach adds value in practice. Ultimately, deriving intrinsic rather than apparent parameter estimates increases confidence in model conclusions, supporting more reliable IVIVE-PBPK-based predictions of drug disposition and transporter-mediated drug-drug interactions without the broad application of sensitivity analysis to inform dosing and regulatory decision-making.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206757","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":"Beyond PROTACs: Conditional Technologies and New Frontiers.","authors":"Ying Yang, Dongsheng Tang, Chunrong Yang","doi":"10.1007/164_2026_843","DOIUrl":"https://doi.org/10.1007/164_2026_843","url":null,"abstract":"<p><p>This chapter surveys the post-PROTAC landscape of targeted protein degradation (TPD), covering conditional activation, new degradation modalities, and proximity-driven editing of post-translational modifications (PTMs). Condition-activated PROTACs harness prodrugs responsive to irradiation or the tumor microenvironment and nanoparticle-based platforms to achieve spatiotemporally resolved protein degradation. The targetable space is further expanded by molecular glues that recruit neosubstrates to E3 ligases, endocytosis-lysosome targeting chimeras that clear extracellular and membrane proteins, and autophagy-lysosome strategies that degrade aggregates and damaged organelles. Ribonuclease-recruiting chimeras achieve targeted RNA degradation, while the induced-proximity concept is repurposed for PTM regulation, enabling targeted glycosylation, acetylation, and phosphorylation and dephosphorylation via the recruitment of glycosyltransferases, acetyltransferases, and kinases and phosphatases. Future advances in all-small-molecule-based conditional systems, brain-targeted delivery, and regulatory frameworks informed by degradation kinetics will embed stimulus sensing and logic-gated operations into intelligent molecular systems, shifting the paradigm toward on-demand proteome and transcriptome rewiring for precision medicine.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181294","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":"Repurposing SGLT2 Inhibitors Beyond Diabetes: Emerging Roles in Cancer Prevention and Therapy.","authors":"Aarajana Shrestha, Idelxy Perez, Jasmine Miles, Lynn Cruz Lopategui, Subrata Deb, Debasish Basak","doi":"10.1007/164_2026_846","DOIUrl":"https://doi.org/10.1007/164_2026_846","url":null,"abstract":"<p><p>Sodium-glucose cotransporter 2 (SGLT2) inhibitors were originally developed as glucose-lowering agents for the management of type 2 diabetes mellitus. Nevertheless, accumulating evidence suggests that their therapeutic potential extends far beyond glycemic control, with emerging roles in cardiovascular and renal protection and, more recently, cancer prevention and therapy. This chapter explores the expanding landscape of SGLT2 inhibitors in oncology, highlighting the molecular mechanisms, preclinical evidence, and evolving clinical implications associated with their anticancer properties. Preclinical studies have demonstrated functional SGLT2 expression in several malignancies, including renal, pancreatic, prostate, liver, and breast cancers, where enhanced glucose uptake supports tumor growth and metabolic adaptation. By inhibiting glucose transport and altering cellular energy metabolism, SGLT2 inhibitors may suppress tumor proliferation, induce apoptosis, and reduce metastatic potential. Additionally, these agents  display indirect anticancer effects through modulation of insulin resistance, reduction of chronic inflammation, attenuation of oxidative stress, and alteration of the tumor microenvironment. Emerging studies also suggest synergistic interactions between SGLT2 inhibitors and established anticancer therapies, including chemotherapy, immunotherapy, and targeted agents. Despite promising experimental findings, clinical evidence remains limited, and several challenges persist regarding optimal patient selection, tumor specificity, dosing strategies, and long-term safety in oncology settings. Furthermore, concerns of adverse effects such as ketoacidosis, genitourinary infections, and volume depletion warrant careful evaluation in cancer population. This review critically examines current knowledge regarding the mechanistic basis and translational potential of SGLT2 inhibitors as adjunctive or repurposed anticancer therapies. By incorporating findings from metabolic research, experimental oncology, and early clinical investigations, this chapter aims to provide a comprehensive overview of how SGLT2 inhibition may represent a novel and promising therapeutic avenue in precision cancer medicine.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136385","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":"Carborane-Based Derivatives as Inhibitors of the Breast Cancer Resistance Protein (ABCG2).","authors":"Philipp Stockmann, Evamarie Hey-Hawkins","doi":"10.1007/164_2026_850","DOIUrl":"https://doi.org/10.1007/164_2026_850","url":null,"abstract":"<p><p>Many chemotherapies are still severely restricted due to cancer cells' resistance to antineoplastic agents. Alongside the constant alteration of cancer itself, neoplastic cells tend to develop a multidrug resistance (MDR), intrinsic or acquired. MDR can result from several unrelated biochemical mechanisms. Altered cell membrane transporters are one of the most extensively implicated causes of MDR, decreasing intracellular drug concentrations to non-therapeutic levels. The upregulation of integral membrane transporters, the ATP-binding cassette transporters (ABCs), is strongly related to increased efflux of chemotherapeutic agents. One of the main efflux transporters associated with MDR is the ABCG2 or Breast Cancer Resistance Protein (BCRP). Thus, selective inhibition of the efflux transporter-mediated excretion of anti-cancer agents represents a valid approach to overcome MDR. This chapter summarizes advances in the design and structural modification of target protein-known scaffolds, such as 5,6,7-trihydroxyflavones, quinazolines, as well as a novel, thus far ABCG2-unrelated scaffold, isoquinolinone. In combination with a carborane moiety (C₂B₁₀H₁₂) as a central pharmacophore and methoxy-based substitution patterns, the modifications can allow enhanced affinities and metabolic stability through the boron-carbon cluster and further allow insight into the pattern-induced relationship between structure and activity. Borcalein and 5,6,7-trimethoxyborcalein, a carborane derivative of 5,6,7-trihydroxyflavone (baicalein) and 5,6,7-trimethoxyflavone, respectively, and a small library of polymethoxylated and carborane-functionalized 2-phenylquinazolin-4-amine derivatives and related carboranylquinazoline amide derivatives are covered in this chapter. A comparison of the most active carborane derivatives with their respective organic phenyl and adamantyl analogs is also included. Biological studies showed reduced toxicity, enhanced inhibitory efficacy, and, most importantly, reversal of drug resistance for most carborane derivatives, rendering such compounds interesting for further studies.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080501","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":"Recent Advances in the Application and Development of Coordinated Radiopharmaceuticals.","authors":"Yinghuai Zhu, Jianghong Cai, Narayan S Hosmane","doi":"10.1007/164_2026_836","DOIUrl":"https://doi.org/10.1007/164_2026_836","url":null,"abstract":"<p><p>The ¹⁷⁷Lu complexes, ¹⁷⁷Lu-DOTATATE and ¹⁷⁷Lu-PSMA-617, have recently been approved by the FDA to treat neuroendocrine tumors and metastatic prostate cancer, respectively. In this chapter, we systematically introduce the classification of radioactive particles and the coordination chemistry and structure-activity relationship of the type complex. In addition, we discuss the challenges encountered in the development of nuclear medicines and propose that artificial intelligence provides new ideas for the design and development of new boron drugs.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060340","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":"Introduction to PBPK Modelling: Core Concepts for Small and Large Molecules.","authors":"Armin Sepp, Iain Gardner","doi":"10.1007/164_2026_855","DOIUrl":"https://doi.org/10.1007/164_2026_855","url":null,"abstract":"<p><p>Physiologically based pharmacokinetic (PBPK) modelling provides the mechanistic frameworks for predicting the absorption, distribution, metabolism, and excretion (ADME) of small- and large-molecule therapeutics, supporting drug development from early discovery through regulatory submission. Although small molecules still constitute the majority of approved drugs, biologics now account for nearly half of the prescription market value, making familiarity with both modelling paradigms essential for DMPK scientists. This review outlines the core structural and mechanistic assumptions of small- and large-molecule PBPK models. Small-molecule models conforming to Lipinski's Rule of Five are typically perfusion-limited, treating organs as well-stirred compartments in which hepatic biotransformation dominates elimination. In contrast, large-molecule models are permeability-limited, incorporating separate vascular, interstitial, and intracellular spaces, with extravasation governed by the two-pore formalism and elimination driven by non-specific macropinocytosis, renal filtration, and target-mediated drug disposition (TMDD). Central to therapeutic antibody disposition is the neonatal Fc receptor (FcRn), whose pH-dependent recycling extends drug half-life and underpins engineering strategies such as pH-switching. We examine differences in dosing, absorption routes, and target repertoires that stem from the drug's physicochemical determinants: molecular weight, charge, and structural rigidity. By outlining these mechanistic distinctions alongside emerging developments, such as permeability-limited models for larger synthetic compounds and biologics-derived targeting modalities, this chapter aims to provide a unified conceptual foundation for applying PBPK modelling across the full spectrum of therapeutic modalities, in support of the Three Pillars of Survival framework linking pharmacokinetics, target engagement, and downstream pharmacology.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030338","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":"Opportunities and Challenges for PBPK Modelling in Specific Populations: Considerations for Paediatrics, Pregnancy, Lactation, Ethnic Differences, and Organ Impairment.","authors":"Xian Pan, Eman El-Khateeb, Udoamaka Ezuruike","doi":"10.1007/164_2026_858","DOIUrl":"https://doi.org/10.1007/164_2026_858","url":null,"abstract":"<p><p>Physiologically based pharmacokinetic (PBPK) modelling represents a key component of model-informed drug development (MIDD), providing a mechanistic framework to predict drug disposition in populations often underrepresented in clinical research. By integrating drug-specific properties with detailed physiological and biochemical parameters, PBPK models bridge knowledge gaps created by ethical, logistical, and safety constraints, enabling evidence-based dosing and supporting more inclusive pharmacotherapy.This chapter examines the application of PBPK modelling across populations in which physiological, pathological, or genetic factors substantially influence pharmacokinetics - namely, paediatrics, pregnant and lactating women, individuals with hepatic or renal impairment, and populations defined by ethnic or pharmacogenomic variability. In each case, PBPK models allow extrapolation from healthy adult data to predict exposure, optimise dosing, and inform study design or regulatory decision-making.Despite their growing impact, challenges remain due to limited physiological data, complex physiological variability, and ethical hurdles. Nevertheless, advances in quantitative systems data, computational techniques, and model qualification frameworks are steadily improving predictive performance. Regulatory agencies increasingly endorse PBPK modelling within MIDD pathways for dose selection, study optimisation, and labelling in specific populations.Looking forward, integration with real-world data, artificial intelligence, and digital health technologies, alongside harmonised regulatory standards, will further enhance model credibility and clinical utility. These developments will reinforce the role of PBPK modelling in ensuring safe, effective, and equitable drug therapy across diverse and physiologically distinct populations.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030300","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 Delivery Strategies for PROTAC.","authors":"Yijing Dang, Zeli Long, Jing Gao, Xingyu Jiang, Yuanyuan Xing, Meiling Wang, Haijun Yu, Zhiai Xu","doi":"10.1007/164_2026_844","DOIUrl":"https://doi.org/10.1007/164_2026_844","url":null,"abstract":"<p><p>Proteolysis-targeting chimeras (PROTACs) have revolutionized drug discovery by enabling event-driven degradation of previously \"undruggable\" proteins via the ubiquitin-proteasome system. Despite their catalytic mechanism and potential to overcome resistance, conventional PROTACs face critical translational bottlenecks: off-target protein degradation causing systemic toxicity, poor pharmacokinetics due to high molecular weight (700-1100 Da) and violation of Lipinski's rule of five, and insufficient tumor accumulation. To address these challenges, diverse delivery strategies have emerged. This chapter systematically examines three progressive tiers of PROTAC delivery: (i) molecular prodrug engineering using stimuli-activatable moieties (light, hypoxia, ROS, enzymes, X-ray, bioorthogonal chemistry), (ii) ligand-mediated active targeting (folate, aptamer, antibody), and (iii) nanoplatform-based systems (polymeric nanoparticles, microneedles, self-assembling nanofibers, biomimetic vesicles). We highlight how these strategies achieve spatiotemporally controlled, tumor-selective protein degradation while minimizing off-tumor toxicity. We also outline future directions including AI-assisted design, logic-gated multi-stimuli systems, oral formulation, and clinical translation. This chapter serves as a road map for developing next-generation intelligent PROTAC delivery systems for precision cancer therapy.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030276","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 Kidney Protection Exerted by SGLT2 Inhibitors.","authors":"Anna Solini, Domenico Tricò","doi":"10.1007/164_2026_847","DOIUrl":"https://doi.org/10.1007/164_2026_847","url":null,"abstract":"<p><p>Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have become foundational therapies for nephroprotection, transforming the management of chronic kidney disease (CKD) beyond the traditional risk factors. This chapter synthesizes evidence from randomized controlled trials and real-world studies demonstrating that SGLT2i consistently reduce albuminuria, slow estimated glomerular filtration rate (eGFR) decline, and lower the risk of hard renal endpoints, including progression to end-stage kidney disease. Early cardiovascular outcome trials first signalled renal benefit as secondary outcomes, which was subsequently confirmed in dedicated renal trials such as CREDENCE, DAPA-CKD, and EMPA-KIDNEY, establishing kidney protection in patients with and without type 2 diabetes and across a broad spectrum of eGFR and albuminuria. Heart failure trials further support renal preservation in high cardiorenal-risk populations. Complementary real-world evidence across multiple health systems corroborates trial findings, extending effectiveness to heterogeneous populations, including older adults and nondiabetic CKD. The chapter also reviews emerging data on combination strategies with GLP-1 receptor agonists or finerenone, long-term treatment considerations, and projections suggesting substantial delays in kidney failure with earlier initiation. Collectively, these data support broad implementation of SGLT2i as core disease-modifying therapy in CKD, while highlighting priority areas for future research in underrepresented populations and optimized combination regimens.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030278","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":"Detection of Environmental Cues by TAAR Family.","authors":"Yue Hao, Hao Wang, Zheng Wang, Qian Li","doi":"10.1007/164_2026_820","DOIUrl":"https://doi.org/10.1007/164_2026_820","url":null,"abstract":"<p><p>The trace amine-associated receptor (TAAR) family is a chemosensory system dedicated to the detection of volatile and water-soluble amine odorants. Unlike canonical odorant receptors (ORs), TAARs function as highly tuned evolutionary sensors that assign innate behavioral valence to critical ecological cues. In this chapter, we examine how TAARs decode the environmental amine landscape to drive survival and social behaviors, focusing on predator avoidance triggered by 2-phenylethylamine, as well as conspecific attraction and social hierarchy formation mediated by trimethylamine. We trace the biophysical adaptations of these receptors from aquatic to terrestrial environments and map the dedicated neural circuits connecting peripheral amine detection to limbic centers. Beyond the olfactory epithelium, we highlight the role of ectopic TAARs as internal biosensors for microbiome- and diet-derived amines across the central nervous, immune, and cardiovascular systems. Finally, we discuss how the contracted human TAAR repertoire continues to influence modern dietary preferences, positioning the TAAR family as a critical interface between environmental sensing and physiological homeostasis.</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":"148955276","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}