Pharmacological research最新文献

{"title":"The TET/5hmC mediated epigenetic landscape in glioma: From molecular mechanisms to therapeutic targeting and future perspectives","authors":"Jiarong He ,&nbsp;Fei Peng ,&nbsp;Ying Xu ,&nbsp;Zhongyue Liu ,&nbsp;Kai Su ,&nbsp;Yang Zhou ,&nbsp;Yugang Jiang ,&nbsp;Ming Wang","doi":"10.1016/j.phrs.2026.108095","DOIUrl":"10.1016/j.phrs.2026.108095","url":null,"abstract":"<div><div>The DNA hydroxymethylation landscape is profoundly disrupted in gliomas, especially glioblastoma, marked by global loss of 5-hydroxymethylcytosine (5hmC) and impaired Ten-eleven translocation (TET) enzyme activity. This review synthesizes evidence that TET family expression and subcellular localization are systematically altered in glioma: TET1 undergoes nuclear exclusion, while TET2 and TET3 show reduced nuclear abundance, directly contributing to 5hmC depletion. The extent of 5hmC loss correlates with tumor grade yet exhibits subtype heterogeneity, including a unique “5hmC-high” glioblastoma subgroup, highlighting the importance of post-transcriptional control of TET protein levels. Upstream regulatory mechanisms involve transcription factors (e.g., SOX2-mediated repression and context-dependent STAT3 activation), non-coding RNAs (such as miR-10b), and epigenetic silencing of TET genes themselves, alongside metabolic and microenvironmental constraints (e.g., D-2-HG from IDH1/2 mutations, hypoxia) that restrict TET catalytic function. Downstream consequences include TET deficiency-driven promoter hypermethylation and MBD-mediated repression of tumor suppressor and differentiation genes, RNA hydroxymethylation-dependent regulation of mRNA stability and splicing, and chromatin reprogramming via interactions with complexes like OGT/COMPASS and PRC2. Functionally, TET inactivation promotes tumor initiation and progression, sustains glioma stem cells, enhances cellular plasticity, drives metabolic reprogramming, and facilitates immune evasion. Emerging therapeutic strategies encompass miRNA antagonists, vitamin C as a TET cofactor, DNMT and HDAC inhibitors, locus-specific epigenetic editing tools (e.g., CRISPR-dCas9 and engineered demethylases), brain-penetrant IDH inhibitors, and novel approaches such as PROTACs and TET mRNA delivery—all requiring precision application due to the context-dependent roles of TET proteins. We further identify critical research gaps, including single-cell and spatial mapping of TET/5hmC dynamics, microenvironmental regulation of TET activity, functional cooperation between TET isoforms, and the development of clinically feasible delivery systems and biomarkers. Addressing these challenges will be essential to translate TET pathway modulation into effective, individualized combination therapies for glioma patients.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108095"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial semi-autonomous inheritance in cardiovascular pathology: Emerging mechanisms and therapeutic opportunities","authors":"Xinyue Xie ,&nbsp;Tianhang Yu ,&nbsp;Wei Deng ,&nbsp;Saiyang Xie","doi":"10.1016/j.phrs.2026.108106","DOIUrl":"10.1016/j.phrs.2026.108106","url":null,"abstract":"<div><div>Cardiovascular diseases (CVDs) continue to be a leading contributor to morbidity and mortality worldwide, with mitochondrial dysfunction emerging as a key pathological hallmark. As semi-autonomous organelles, mitochondria regulate cellular energy metabolism and homeostasis through intricate interactions between nuclear and mitochondrial genomes. This review synthesizes recent advances in understanding mitochondrial semi-autonomous inheritance mechanisms in cardiac pathology, encompassing mtDNA dynamics, epigenetic and non-epigenetic modifications, mtDNA release-induced inflammation, and mito-nuclear communication. Impaired regulation of the aforementioned processes causes disruption to the mitochondrial function, inducing cardiac remodeling and CVD progression. Here, we reveal novel therapeutic opportunities, including natural and pharmaceutical modulators, mitochondrial gene-editing technologies, and ncRNA-based interventions which can potentially restore mitochondrial homeostasis. Moreover, several challenges such as achieving precise drug targeting and implementation of real-time efficacy monitoring remain to be resolved. Future research should develop strategies to close these gaps, identify the context-dependent mechanisms, and advance translational applications to improve the prognosis of CVDs.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108106"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crosstalk mechanisms among gut microbiota, novel programmed cell death, and macrophage polarization","authors":"Zilu Zhang ,&nbsp;Hewei Qin","doi":"10.1016/j.phrs.2026.108091","DOIUrl":"10.1016/j.phrs.2026.108091","url":null,"abstract":"<div><div>Several disease conditions are associated with the abnormal activation of pyroptosis, ferroptosis, necroptosis, cuproptosis, and disulfidptosis, as well as dysregulated macrophage polarization, which collectively serve as hallmarks of tissue damage and organ dysfunction. Importantly, these emerging forms of programmed cell death are closely linked to intestinal microbiota homeostasis. The gut microbiota constitutes a key ecosystem that regulates host metabolism, immunity, and overall physiological balance. When gut microbiota dysbiosis occurs, it promotes the production of harmful metabolites and activates inflammatory signaling pathways. This leads to metabolic disturbances and chronic inflammation, which in turn can induce pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis, and polarization of macrophages toward the M1 phenotype. Therefore, a deeper understanding of the dynamic regulation of the gut microbiota in these forms of cell death and macrophage polarization is essential for comprehending the progression of related diseases. In this review, we systematically summarize the impact of gut microbiota and its metabolite alterations on the regulation of these novel programmed cell death pathways and macrophage polarization, aiming to advance the understanding of related disease pathogenesis and provide a theoretical foundation for potential therapeutic strategies.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108091"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145945567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunometabolic reprogramming of macrophages: Emerging roles in skeletal muscle regeneration and therapeutic perspectives","authors":"Si-jing Li ,&nbsp;Xing-ling He ,&nbsp;Xiao-jiao Zhang ,&nbsp;Zi-ru Li ,&nbsp;Hui-lin Liu ,&nbsp;Yi-hui Zhang ,&nbsp;Min-qi Lu ,&nbsp;Jia-hui Chen ,&nbsp;Xiao-ming Dong ,&nbsp;Wen-jie Long ,&nbsp;Lu Lu ,&nbsp;Zhong-qi Yang ,&nbsp;Shi-hao Ni","doi":"10.1016/j.phrs.2026.108109","DOIUrl":"10.1016/j.phrs.2026.108109","url":null,"abstract":"<div><div>Skeletal muscle regeneration is a complex and strictly regulated process that involves complex interactions between immune cells, muscle-resident progenitor cells, and stromal components. Macrophages play a central role in this process by coordinating immune responses, supporting regeneration, and promoting tissue remodeling through phenotypic transitions that respond to environmental cues. Under physiological conditions, these transitions ensure efficient tissue restoration. However, in pathological settings or conditions such as aging, muscular dystrophy, cancer cachexia, and metabolic disorders, macrophage function becomes dysregulated. This situation often leads to persistent inflammation, excessive fibrosis, and impaired regeneration of muscle tissue. Recent advances in single-cell and spatial transcriptomics technologies have revealed the remarkable heterogeneity of macrophage subpopulations within skeletal muscle. These findings emphasize the importance of immunometabolic programming as a key driver of macrophage plasticity. Shifts in glucose metabolism, oxidative phosphorylation, lipid utilization, and amino acid pathways critically influence the polarization of macrophages and their interactions with surrounding cells. Moreover, metabolic signals from the tissue microenvironment, circulating factors, and muscle-resident cells create a dynamic network of metabolic crosstalk that shapes macrophage behavior. This review provides a comprehensive summary of how macrophage immunometabolism regulates skeletal muscle regeneration in both acute injury and chronic disease. It highlights core metabolic pathways, macrophage-centered intercellular communication, and emerging therapeutic strategies that aim to reprogram macrophage metabolism for a regenerative benefit. In addition, key challenges and future directions for translating these insights into effective interventions for muscle wasting conditions are discussed.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108109"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146038221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired PARP1-dependent DNA repair in MORC2 mutations drives axonal degeneration in Charcot-Marie-Tooth disease subtype 2Z and spinal muscular atrophy-like neuromotor disorders","authors":"Mengli Wang ,&nbsp;Honglan Yang ,&nbsp;Zhongzheng Li ,&nbsp;Sen Zeng ,&nbsp;Ke Xu ,&nbsp;Binghao Wang ,&nbsp;Yongzhi Xie ,&nbsp;Qingping Wang ,&nbsp;Zhuolin Su ,&nbsp;Mingri Zhao ,&nbsp;Yiti Zhang ,&nbsp;Mujun Liu ,&nbsp;Beisha Tang ,&nbsp;Xionghao Liu ,&nbsp;Ruxu Zhang","doi":"10.1016/j.phrs.2026.108103","DOIUrl":"10.1016/j.phrs.2026.108103","url":null,"abstract":"<div><div><em>MORC2</em> mutations are associated with a spectrum of neuromotor disorders, including Charcot-Marie-Tooth disease subtype 2Z (CMT2Z) and a spinal muscular atrophy (SMA)-like phenotype. However, the mechanisms underlying these conditions remain unclear. In this study, we used iPSC-derived motor neurons (iPSC-MNs) carrying three distinct <em>MORC2</em> mutations, p.S87L (SMA-like), p.Q400R, and p.D466N (CMT2Z), to examine their effects on cellular processes. Our results show that <em>MORC2</em> mutations induce apoptosis, DNA damage, and axonal pathology, including shortened neurites, elevated axonal breakage, and increased axonal swellings, with the most severe phenotypes observed in iPSC-MNs harboring p.S87L. Mechanistically, these mutations impair DNA repair by disrupting the interaction between <em>MORC2</em> and PARP1, leading to reduced PARP1 activity and expression, as well as diminished DNA repair protein expression and recruitment. Notably, inhibition of PAR degradation with PDD restored PAR levels, reduced DNA damage accumulation, and ameliorated axonal pathology in p.S87L-mutant iPSC-MNs. These findings demonstrate that <em>MORC2</em> mutations impair DNA repair through PARP1-dependent pathways, contributing to axonal degeneration. Targeting the PAR signaling pathway with inhibitors such as PDD may therefore represent a promising therapeutic avenue for MORC2-related neuromotor disorders.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108103"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Live cell luminescence-based Gαq-PLC-β interaction assay: Development and application at the serotonin 5-HT2A receptor","authors":"Eline Pottie ,&nbsp;Christophe P. Stove","doi":"10.1016/j.phrs.2026.108094","DOIUrl":"10.1016/j.phrs.2026.108094","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) remain among the most important drug targets. To characterize their ligands’ activity, a range of <em>in vitro</em> assays is available, all with their inherent advantages and limitations. In the Gα_q signaling pathway, the interaction between Gα_q and phospholipase C (PLC-)β is a receptor-proximal event, and its monitoring does not require modification of the GPCR. With this in mind, we set out to develop a luminescence-based assay gauging this interaction. The resulting assay format encompassed functional complementation of a split nanoluciferase following the interaction of SmBiT, N-terminally fused to PLC-β, with LgBiT, intramolecularly integrated within Gα_q. When applied to assess activation of the Gα_q-coupled serotonin 2 A receptor (5-HT_2AR), an excellent assay performance was demonstrated, as evidenced by an auspicious Z’-factor of 0.75 and by confirming the specificity for both the GPCR and the Gα_q signaling pathway. The optimized Gα_q-PLC-β assay was successfully applied on a diverse panel of 5-HT_2AR ligands and the resulting output was compared with that of a more upstream miniGα_q recruitment assay, and more downstream IP₁ accumulation and Ca²⁺ mobilization assays. Overall, the Gα_q-PLC-β assay yielded efficacy, potency and relative activity data that correlated very well with those obtained with the IP₁ accumulation and miniGα_q recruitment assays, although with the former two assays consistently higher potencies and a smaller range of efficacies were observed. Comparison with the Ca²⁺ mobilization assay did not yield such good correlation, presumably because of kinetic implications. Last, the Gα_q-PLC-β interaction assay allowed to detect signals emerging from endogenously expressed GPCRs, indicative of its broad applicability.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108094"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial pyruvate dehydrogenase kinase 1 drives bevacizumab resistance and malignant phenotype of TNBC by enhancing mitophagy","authors":"Yan Ye ,&nbsp;Qian Zeng ,&nbsp;Zuli Ou ,&nbsp;Xiaoqian Ju ,&nbsp;Qingyu Liao ,&nbsp;Canling Li ,&nbsp;Dian Zhang ,&nbsp;Yu Wei ,&nbsp;Xiang Zhang ,&nbsp;Kejia Wu ,&nbsp;Tingmei Chen","doi":"10.1016/j.phrs.2025.108081","DOIUrl":"10.1016/j.phrs.2025.108081","url":null,"abstract":"<div><div>Bevacizumab is an anti-angiogenic agent widely used in neoadjuvant chemotherapy for advanced triple-negative breast cancer (TNBC). TNBC patients frequently acquire resistance to bevacizumab due to the hypoxic tumor microenvironment, yet the underlying molecular mechanism remains unclear. Here, we demonstrate that mitochondrial reprogramming under hypoxia is crucial for resistance to bevacizumab. Mechanically, prolonged hypoxia causes the glycolytic pathway enzyme PDK1 to accumulate inside mitochondria. In mitochondria, PDK1 exerts its non-canonical function to phosphorylate mitochondrial protein Prohibitin 2 (PHB2) at Ser190. Phosphorylation at Ser190 stabilizes PHB2 and enhances its binding with LC3, thereby initiating mitophagy. Functionally, mitochondrial PDK1 (mito-PDK1) initiates mitophagy in response to hypoxia-induced mitochondrial damage and promotes the malignant phenotype of TNBC cells. In xenograft tumors, inhibiting the function of mito-PDK1 enhances the sensitivity to bevacizumab. Collectively, our findings identify the crucial function and mechanism of mito-PDK1 in TNBC. Targeting mito-PDK1 function may emerge as a novel therapeutic strategy to address acquired resistance to bevacizumab.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108081"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism of μ-opioid receptor inhibition by orphan GPR88","authors":"Claudia Llinas del Torrent ,&nbsp;Iu Raïch ,&nbsp;Berta Carrasco-Martinez ,&nbsp;Jaume Lillo ,&nbsp;Maria Gallo ,&nbsp;David Andreu ,&nbsp;Leonardo Pardo ,&nbsp;Gemma Navarro","doi":"10.1016/j.phrs.2025.108084","DOIUrl":"10.1016/j.phrs.2025.108084","url":null,"abstract":"<div><div>From the approximately 800 members of the G protein-coupled receptor (GPCR) family, more than 100 remain orphans (oGPCRs). There is evidence indicating that some oGPCRs may carry out a physiological role independently from endogenous ligands; this includes forming heteromers with other GPCRs and altering their functional and pharmacological properties via allosteric interactions. Recent studies have shown that some of these oGPCRs, e.g. GPR88 and GPR139, allosterically inhibit opioid activity by interacting with the μ-opioid receptor (μOR). Here, we have focused on the characterization of the interaction between GPR88 and µOR and the allosteric mechanism of inhibition. We confirmed that GPR88 inhibits µOR function in striatal neuronal primary cultures. Moreover, using a peptide-interfering approach combined with biophysical and biochemical techniques, we identified that GPR88 and µOR interact via transmembrane helix 6. A combination of molecular dynamic simulations and site-directed mutagenesis have allowed to propose that the negative regulatory role of GPR88 on µOR is due to the Q298^6.49 side chain of GPR88.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108084"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145940633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low, non-psychedelic doses of psilocybin as a novel treatment for MASLD, obesity and type 2 diabetes via 5-HT2B receptor-dependent mechanisms","authors":"Martina Colognesi ,&nbsp;Daniela Gabbia ,&nbsp;Anna Signor ,&nbsp;Miles Sarill ,&nbsp;Lucia Centofanti ,&nbsp;Andrea Rinaldi ,&nbsp;Luciano Cascione ,&nbsp;Sara Nunziata ,&nbsp;Marco Banzato ,&nbsp;Andrea Mattarei ,&nbsp;Giovanna Finzi ,&nbsp;Sonia Sonda ,&nbsp;Diana Pendin ,&nbsp;Ilaria Zanotto ,&nbsp;Stefano Comai ,&nbsp;Gianfranco Pasut ,&nbsp;Abdullah Alajati ,&nbsp;Miriam Saponaro ,&nbsp;Loredana Bucciarelli ,&nbsp;Maria Elena Lunati ,&nbsp;Sara De Martin","doi":"10.1016/j.phrs.2025.108080","DOIUrl":"10.1016/j.phrs.2025.108080","url":null,"abstract":"<div><div>The therapeutic potential of low, non-psychedelic doses of psilocybin, a fungal tryptamine alkaloid, was investigated in metabolic disorders including obesity, type 2 diabetes mellitus (T2DM), and liver steatosis. Mice fed a high-fat/high-fructose diet received chronic treatment with psilocybin (0.05 mg/kg) for 12 weeks. Body weight, liver histology, insulin sensitivity, and skeletal muscle function were assessed, and hepatic and muscle tissues underwent transcriptomic and lipidomic analyses. The role of three serotonin receptors (5-HT2A, 5-HT2B, and 5-HT2C) in psilocybin-induced metabolic effects was examined in human cell lines using pharmacological and CRISPR/Cas9-based genetic approaches. Low-dose psilocybin reduced body-weight gain, liver steatosis, hyperglycaemia, and insulin resistance without eliciting central nervous system effects. Multi-omics analyses revealed near-complete normalization of disrupted hepatic lipid and carbohydrate metabolism pathways. Psilocybin also improved muscle strength and function, potentially through restoration of leptin sensitivity. Mechanistic studies demonstrated that these metabolic benefits were independent of the canonical psychedelic target 5-HT2A and instead resulted from antagonism of the serotonin 5-HT2B receptor in the liver. Overall, chronic low-dose psilocybin exerts broad metabolic benefits via a hepatic 5-HT2B-dependent mechanism, distinct from its psychedelic effects, supporting its potential as a novel therapeutic strategy for liver steatosis, obesity, T2DM, and sarcopenia.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108080"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Properties of FDA-approved small molecule protein kinase inhibitors: A 2026 update","authors":"Robert Roskoski Jr.","doi":"10.1016/j.phrs.2026.108107","DOIUrl":"10.1016/j.phrs.2026.108107","url":null,"abstract":"<div><div>Because of the dysregulation of protein kinase activity in many neoplastic and inflammatory diseases, protein kinases are among the most significant drug targets in the 21st century. Of the 94 FDA-approved protein kinase inhibitors, ten were approved in 2025. Of these drugs, six target dual specificity protein kinases (MEK1/2), fourteen inhibit protein-serine/threonine kinases, twenty-six block nonreceptor protein-tyrosine kinases, and 48 target receptor protein-tyrosine kinases. Most of these drugs (≈ 80) are prescribed for the management of neoplasms and others are used for the treatment of inflammatory and miscellaneous diseases. Of the 94 FDA-approved agents, about two dozen are used in the treatment of multiple diseases. The following ten drugs received FDA approval in 2025 – avutometinib (inhibiting MEK1/2 in serous ovarian carcinomas), defactinib (blocking FAK in low grade serous ovarian carcinomas), delgocitinib (antagonizing the JAK family in hand eczema), mirdametinib (inhibiting MEK1/2 in type I neurofibromatosis), remibrutinib (blocking BTK in chronic spontaneous urticaria), rilzabrutinib (antagonizing BTK in chronic immune thrombocytopenia), sunvozertinib (blocking mutant exon 21 insertion EGFR NSCLC), taletrectinib (inhibiting mutant <em>ROS1</em> in NSCLC), vimseltinib (blocking CSF1R in tenosynovial giant cell tumors), and zongertinib (antagonizing mutant <em>HER2</em> in NSCLC). Ninety of the approved protein kinase blockers are orally bioavailable. This article summarizes the physicochemical properties of all 94 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, ligand efficiency, lipophilic efficiency, polar surface area, and solubility. A total of 45 of the 94 FDA-approved drugs have a least one Lipinski rule of five violation.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108107"},"PeriodicalIF":10.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}