Over the past decade, research associated with organoids has entered a golden era, marking a significant shift in the biomedical landscape. Organoids have been widely applied in the industrial sector and have gained recognition from regulatory authorities. However, amid this rapid expansion, a comprehensive and precise overview of the field has been lacking. Our review aims to fill this gap by presenting a comprehensive overview of the regulations and prospects for the development of investigational new drugs (INDs) using organoids. Drawing on our extensive experience in academic research and industrial applications, we meticulously analyzed the organoid field from two distinct perspectives. We explored the synergies between organoids and cutting-edge technologies such as single-cell omics, which highlights their crucial role in customizing personalized medicines, improving high-throughput drug screening, and establishing physiologically relevant disease models. Organoids offer advantages over traditional animal models, including high throughput, rapid results, cost-effectiveness, and strong clinical relevance. Our analysis delves into supportive policies from regulatory bodies such as the European Medicines Agency (EMA), Food and Drug Administration (FDA), and Center for Drug Evaluation (CDE) for the use of organoids. Our comprehensive analysis and reflective discourse provide a deep dive into the current landscape of drugs derived from organoids that have obtained IND status and the subsequent progress in clinical trials. We cautiously anticipate challenges and future directions in organoid research, particularly in terms of its potential impact on personalized patient care, novel avenues for drug discovery, and clinical research. In summary, our review presents a comprehensive exploration of organoid technology and prospects for the development of INDs using organoids, thereby providing reflections, summaries, and projections that can be beneficial for current researchers.
To describe the development and implementation of a standardized, pharmacy-led assessment of risk (AOR) process for investigational products (IPs) in compliance with United States Pharmacopeia (USP) chapter <800> across a large academic health network. USP <800> mandates institutions to maintain a hazardous drug list but offers limited guidance for investigational agents. The US National Institute for Occupational Safety and Health (NIOSH) has a published list of hazardous drugs that institutions should reference. However, the list only includes agents approved through December 2015, leaving a large gap in hazardous drug standardization for marketed products, providing less precedent for those working with investigational agents. In response, a multidisciplinary workgroup led by pharmacy services developed a system-wide IP AOR process. Two distinct tools incorporating toxicological and biosafety criteria were created to assess small-molecule and biopharmaceutical agents. A centralized database and oversight committee were established to ensure consistency, transparency, and regulatory compliance. As of July 2025, 255 IPs were assessed: 8 high-risk hazardous, 126 low-risk hazardous, and 121 nonhazardous agents. The process has enabled appropriate labeling, safe handling, and efficient review workflows across research pharmacies. The IP AOR process demonstrates the essential role of pharmacists in operationalizing USP <800> requirements for investigational drugs. This model supports occupational safety, regulatory compliance, and scalable implementation across health systems engaged in clinical research. The process outlined in this manuscript is applicable to both investigational agents and any newly marketed drugs being brought into an institution that haven't been reviewed by NIOSH for inclusion on their list.
The sulfonamide motif is widely used in the design of small molecules owing to its enzymatic stability but also its potentiality to improve target engagement and to provide a beneficial ADME profile. From the commercialization of Prontosil® in 1933 until 2023, a total of 91 compounds containing a sulfonamide moiety have received approval from the FDA. In parallel, analysis of the ChEMBl database revealed that 200 sulfonamide-containing compounds have entered clinical trials between 1998 and 2023. This review aims to present an exhaustive assessment of the sulfonamide motif in approved and investigational drugs, encompassing its pharmacokinetic and pharmacological properties, physicochemical properties, biological targets and temporal trends. Our analysis reveals a shift from traditional applications in antibacterials and diuretics toward modern oncology and antiviral therapeutics, with investigational compounds increasingly targeting GPCRs and kinases. Using selected case studies of approved drugs, we demonstrate that sulfonamide incorporation can enhance biological activity and modulate drug-like properties, providing evidence-based guidance to medicinal chemists.
Cutaneous T-cell lymphomas (CTCLs) are a rare group of T-cell lymphomas originating from skin-homing T-lymphocytes. While patients with early-stage disease may have an indolent disease course and excellent survival rates, patients with advanced-stage disease and the aggressive leukemic variant Sézary syndrome (SS) have poor outcomes with poor responses to therapy and short durations of response. New and better treatments are urgently needed for these patients. This review describes the current treatment landscape including underlying disease biology, diagnosis and staging, approaches to therapy with novel FDA-approved agents including brentuximab vedotin, mogamulizumab, and denileukin diftitiox-cdxl. Novel and upcoming biomarkers, drugs, and therapeutic strategies are additionally covered in detail with a focus on safety, efficacy, and compartment-specific effects. Recent years have seen a shift away from chemotherapy with the approval of targeted therapies like mogamulizumab, brentuximab vedotin, and denileukin diftitox-cxdl. Though these novel agents have improved outcomes for patients with advanced-stage CTCL, most patients will continue to experience relapses. Emerging agents, including lacutamab, resminostat, and immune checkpoint inhibitors and biomarkers including CD5, CD70, and CD47/Sirpα represent the next frontier in maintaining durable remissions and improving quality of life (QoL) for these patients.
Objective: To systematically summarize the research progress of clinical trials on breast cancer drugs in China from 2011 to 2022, as well as provide an overview of the marketed drugs. The goal is to offer data and decision-making evidence for relevant departments. Methods: Based on the registration database of the China National Medical Products Administration's Clinical Trial Registration and Information Disclosure Platform, as well as data from the domestic and imported drug query systems, an analysis was conducted on clinical trials of breast cancer drugs, including information on investigational drugs and marketed drugs from January 1, 2011, to December 31, 2022. The study compared differences between Chinese and foreign enterprises in terms of trial scope, trial phases, number of treatment lines, drug types, and mechanisms of action. Results: From 2011 to 2022, a total of 401 clinical trials for breast cancer were registered in China, accounting for 8.0% of the country's overall anti-tumor clinical trials (401/5 011), with 304 trials (75.8%) initiated by domestic enterprises. Over the past decade, clinical trials for breast cancer showed fluctuating growth, reaching a peak of 84 trials in 2020. These trials involved 254 drugs, with 156 (61.4%) being original drugs and 174 (68.5%) being targeted therapies. The most focused targets included human epidermal growth factor receptor 2 (HER-2), cyclin-dependent kinases 4/6 (CDK4/6), and estrogen receptors (ER). There are 50 drugs targeting HER-2 (28.7%), 35 targeting CDK4/6 (20.1%), and 31 targeting ER (17.8%). During the period from 2011 to 2022, a total of 15 drugs for treating breast cancer were approved and launched in China, covering 19 indications. Among these, 7 indications are for adjuvant or neoadjuvant therapy of early-stage breast cancer, and 12 indications are for advanced breast cancer. Conclusions: Substantial achievements have been made in the development of new breast cancer drugs in China from 2011 to 2022. However, there remains a significant gap in the innovation capabilities of domestic pharmaceutical companies compared to international counterparts in the field of breast cancer. Future efforts should be directed towards strengthening research and development in breast cancer, exploring new target points, and investigating combination therapy mechanisms. 目的： 系统分析2011—2022年中国乳腺癌药物临床试验的研究进展及上市药物概况，为相关部门提供数据及决策证据。 方法： 基于中国国家药品监督管理局药物临床试验登记与信息公示平台及国产药品及进口药品数据查询系统，分析2011年1月1日至2022年12月31日乳腺癌药物临床试验、试验用药品及上市药物信息，比较中国企业和国外企业在试验范围、试验分期、治疗线数及药物类型、作用机制等方面的差异。 结果： 2011—2022年，中国共注册登记401项乳腺癌药物临床试验，占中国抗肿瘤药物临床试验的8.0%（401/5 011），其中国内企业发起304项（75.8%）。近10年乳腺癌临床试验数量呈波动式增长，2020年达峰（84项）。上述试验共涉及254种药物，156种（61.4%）为原研药，174种（68.5%）为靶向药，其中，人表皮生长因子受体2（HER-2）、细胞周期蛋白依赖性激酶4/6（CDK4/6）、雌激素受体（ER）是乳腺癌临床试验更受关注的3个靶点，靶向HER-2的药物有50种（28.7%），靶向CDK4/6的35种（20.1%），靶向ER的31种（17.8%）。2011—2022年间共有15种治疗乳腺癌的药物在中国获批上市，涉及19种适应证，其中7个适应证针对早期乳腺癌的辅助或新辅助治疗，12个适应证为晚期乳腺癌。 结论： 中国乳腺癌新药研发在2011—2022年取得了巨大成果，但是国内药企在乳腺癌方面的新药创新能力较国际仍有较大差距，靶点分布有同质化趋向，建议国内企业挖掘中国乳腺癌人群特点，加大创新乳腺癌药物研发投入。.
Nitrogen-containing heterocycles (N-Hets) are among the most prevalent and versatile structural motifs in pharmaceuticals, serving as key scaffolds in over 85% of biologically active small molecules. Their structural diversity and functional versatility have made them integral components of both U.S. Food and Drug Administration (FDA) approved and investigational drug molecules, modulating biological activity across a range of molecular targets. In 2025, the FDA approved 26 small-molecule drugs featuring N-Het frameworks, spanning multiple therapeutic areas, including oncology, metabolic disorders, infectious diseases, and rare/orphan conditions. This review offers a comprehensive overview of these newly approved compounds, emphasizing their biological activity and synthetic approaches. Special attention is given to drug-target interactions, focusing on receptor binding and highlighting the important role of N-Hets in medicinal chemistry. By exploiting the intrinsic chemical properties of N-Hets and leveraging modern synthetic methodologies, these scaffolds continue to drive the discovery of therapeutically relevant molecules, highlighting their sustained significance in modern drug discovery.
Glioma is a highly malignant brain tumor with limited treatment options. We employed the Computational Analysis of Novel Drug Opportunities (CANDO) platform for multiscale therapeutic discovery to predict new glioma therapies. We began by computing interaction scores between extensive libraries of drugs/compounds and proteins to generate "interaction signatures" that model compound behavior on a proteomic scale. Compounds with signatures most similar to those of drugs approved for a given indication were considered potential treatments. These compounds were further ranked by degree of consensus in corresponding similarity lists. We benchmarked performance by measuring the recovery of approved drugs in these similarity and consensus lists at various cutoffs, using multiple metrics and comparing results to random controls and performance across all indications. Compounds ranked highly by consensus but not previously associated with the indication of interest were considered new predictions. Our benchmarking results showed that CANDO improved accuracy in identifying glioma-associated drugs across all cutoffs compared to random controls. Our predictions, supported by literature-based analysis, identified 24 potential glioma treatments, including approved drugs like vitamin D, taxanes, vinca alkaloids, topoisomerase inhibitors, and folic acid, as well as investigational compounds such as ginsenosides, chrysin, resiniferatoxin, and cryptotanshinone. Further functional annotation-based analysis of the top targets with the strongest interactions to these predictions identified Vitamin D3 receptor, thyroid hormone receptor, acetylcholinesterase, cyclin-dependent kinase 2, tubulin alpha chain, dihydrofolate reductase, and thymidylate synthase. These findings indicate that CANDO's multitarget, multiscale framework is effective in identifying glioma drug candidates thereby informing new strategies for improving treatment.Scientific contribution (1) We present a robust, multiscale drug discovery framework that accurately recovers known glioma therapies and uncovers 24 novel candidates with strong literature and mechanistic support. (2) By modeling compound behavior across the proteome, our method pinpoints key targets-including VDR, CDK2, and DHFR-implicated in glioma biology. (3) This work positions CANDO as a powerful tool for rational repurposing and discovery of urgently needed treatments for aggressive brain tumors.
Peripheral artery disease (PAD) induces chronic limb ischemia that affects downstream skeletal muscle and leads to ischemic myopathy. Chronic ischemia results in mitochondrial dysfunction, oxidative stress, fiber-type shift, proteolysis, and anabolic resistance, contributing to reduced endurance and persistent weakness despite revascularization. This narrative review provides a clinically oriented synthesis of PAD-related muscle pathology, pragmatic approaches to assessing muscle mass and quality, and current strategies to preserve or restore muscle health. Chronic ischemia impairs mitochondrial biogenesis, increases reactive oxygen species, activates ubiquitin-proteasome and autophagy-lysosome pathways, and suppresses IGF-1/Akt/mTOR signaling, resulting in muscle atrophy and qualitative degeneration. Endothelial dysfunction and pro-inflammatory macrophage polarization further limit regeneration. Assessment begins with the ankle-brachial index and functional screening, followed by segmental bioimpedance or bedside ultrasound, with selective computed tomography or magnetic resonance imaging. Although exercise improves walking performance, endurance-only programs may inadequately preserve limb muscle, whereas resistance-inclusive training better maintains muscle mass and quality. Revascularization restores perfusion and mitigates ischemia, thereby preparing a physiological environment that supports, but does not by itself ensure, rehabilitation-driven improvements in skeletal muscle and functional recovery. Conventional PAD drugs reduce vascular risk but show limited direct muscle effects; mechanism-based therapies remain investigational. Recognizing skeletal muscle as a therapeutic target supports an integrated management approach combining revascularization, resistance-inclusive exercise, nutritional optimization, and emerging muscle-directed therapies to improve mobility and clinical outcomes.
Ulcerative colitis is a chronic inflammatory bowel disease with rising global prevalence. Despite therapeutic advances including biologic agents targeting tumor necrosis factor-alpha, integrins, and interleukin pathways, alongside Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators, substantial unmet needs persist in moderate to severe disease. Current advanced therapies achieve clinical response rates of only 30-60% in trials, with approximately 20% of patients requiring hospitalization and 7% undergoing colectomy within five years of diagnosis. The therapeutic pipeline for moderate to severe ulcerative colitis currently encompasses over 100 investigational agents in Phase II and III clinical development. Emerging mechanisms include next-generation Janus kinase and tyrosine kinase 2 inhibitors with enhanced selectivity, novel cell trafficking modulators, advanced tumor necrosis factor-alpha inhibition strategies, and selective interleukin-23 pathway antagonists. Tumor necrosis factor-like ligand 1A pathway inhibitors demonstrate particularly robust efficacy in early trials, with clinical remission rates exceeding 25% compared to less than 2% for placebo. Additional promising approaches target immune checkpoint pathways, receptor-interacting protein kinase 1, and intracellular signaling cascades. innovative combination therapy approaches demonstrated to achieve superior response rates compared to monotherapy. The convergence of novel therapeutic targets, gut-selective compounds minimizing systemic immunosuppression, and biomarker-guided therapy selection represents a paradigm shift toward precision medicine. These advances hold genuine promise for transforming moderate to severe ulcerative colitis management.
Pituitary surgery is the primary therapy for most patients with acromegaly. Medical therapy has an important, albeit adjunctive role in the management of patients with persistent disease after surgery. However, primary medical therapy can be appropriate as an option in select patients. Medical therapies in current use for acromegaly are somatostatin receptor ligands (SRLs) (octreotide long-acting release [LAR], octreotide acetate, lanreotide depot, octreotide subcutaneous (SC) depot, pasireotide LAR, oral octreotide, paltusotine), dopamine agonists (cabergoline) and growth hormone receptor antagonists (pegvisomant). These are often efficacious and generally well tolerated. However, a particular pharmaceutical agent may not meet the needs of individual patients because of intolerance, contraindications to their use, lack of sustained efficacy, or decreased quality of life. Several investigational drugs are in development towards addressing unmet needs of patients with acromegaly, including new formulations of SRLs (lanreotide prolonged-release formulation, Debio 4126, pasireotide SC depot), novel SRLs (somatoprim, HTL0030310), monoclonal antibodies against growth hormone, and new growth hormone receptor antagonists. Current and emerging therapies are offering renewed hope for disease control. More studies including comparator agents, identification of accurate biomarkers and models predictive of clinical effectiveness may further improve the care of patients with acromegaly.
Dermatoporosis (DP) or chronic cutaneous fragility syndrome has traditionally been linked to extracellular matrix (ECM) dehydration, reduced cellular turnover, epidermal thinning, and vascular fragility. However, recent imaging methods and clinical evidence indicate that the dermoepidermal junction (DEJ) might be the earliest change reflecting DP reversal. To propose a new mechanistic process in which the DEJ acts as the initiation point for reversing the DP. The process is supported by clinical and imaging evidence, as well as independent literature on DEJ biology. A combination of clinical and investigational findings, published theoretical models, and evidence from wound-healing, skin-longevity reports, ex vivo model analyses, and device-based interventions formed the basis for the scientific narrative. Cumulative evidence suggests that an initial change in the DEJ, along with structural restoration, appears to trigger or initiate regenerative processes in the ECM and epidermis. These include the renewal of basal stem cells following adhesion signaling in the basement membrane; ECM remodeling through improved communication between the dermis and epidermis, along with enhanced fibroblast interactions involving collagen and elastin; and finally, ECM remodeling and stabilization of basement membrane anchoring provides support and stability to blood vessels, protecting them from recurrent injury. The DEJ acts as a bridge between the epidermis and dermis, providing structural support while also triggering signaling cascades that promote a regenerative environment, contributing to DEJ reversal. Targeting the DEJ could be a logical therapeutic approach, establishing a new paradigm for biomarker analysis and an intervention site for regenerative initiation.  .
The purpose of this article is to discuss the pathophysiology, epidemiology, clinical assessment, and management of elevated lipoprotein(a) (Lp(a)) levels in atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). Lp(a) is a unique lipoprotein consisting of 2 components: a low-density lipoprotein (LDL) moiety and a single molecule of apolipoprotein(a) (apo(a)), which binds to apolipoprotein B in the LDL moiety. The cholesterol content of the LDL moiety promotes atherosclerosis while apo(a) confers additional atherogenic and inflammatory properties to Lp(a). Lp(a) is an independent and causal risk factor for ASCVD and CAVS as well as all-cause mortality. Elevations in Lp(a) levels are genetically determined with minimal reductions observed in response to nonpharmacological risk factor modification. Currently available lipid-lowering drugs produce minimal or only modest percent changes in Lp(a) levels. As a consequence, Lp(a) is rarely measured in clinical practice. Several investigational agents designed to specifically target Lp(a) reduce levels by 80% to 100%. These agents work by decreasing the synthesis of apo(a) or by inhibiting the binding of apo(a) to apolipoprotein B. Phase 3 ASCVD outcome trials for several of these agents have completed enrollment. Elevated Lp(a) levels are a known risk factor for ASCVD and CAVS. Several investigational drugs produce 80% to 100% reductions in Lp(a) levels. However, until these therapies are proven to lead to favorable clinical outcomes, management of patients with elevated Lp(a) levels will continue to be limited to early and intensive ASCVD risk factor management.
Health-system pharmacists play a crucial role in monitoring the pharmaceutical pipeline to manage formularies, allocate resources, and optimize clinical programs for new therapies. This article aims to support pharmacists by providing updates on new and anticipated novel drug approvals. Selected drug approvals anticipated in the 12-month period covering the 4 quarters of 2026 are reviewed. The analysis emphasizes drugs expected to have significant clinical and financial impact in hospitals and clinics, as selected from 52 novel drugs awaiting US Food and Drug Administration approval. This year's pipeline features novel therapies for various disease states, including rare and inherited genetic disorders as well as immunologic and inflammatory diseases, and continued advancements in both targeted oncology and gene therapies. Novel therapies continue to strengthen the current drug pipeline.
Challenges to medication administration arise in children when pediatric-friendly (PF) formulations are lacking. This study examines the extent to which PF formulations were developed for use in pediatric trials of drugs awarded 6-months of patent extension under a written request (WR). Publicly accessible and proprietary data were aggregated to characterize the formulations used in studies submitted to the U.S. FDA in support of pediatric labeling for WRs issued through September 2025. From 1998-2025, exclusivity was awarded to 321 unique sponsor:drug pairs satisfying the requirements of a WR. A majority, (235/321), received a new or updated pediatric indication and nearly all (310/321) resulted in pediatric labeling. Drugs intended for oral administration (n = 213) were supported by 304 studies. The majority (173/304) exclusively studied adult solid dosage forms (SDF), a minority (129/304) used at least one PF dosage form, and 2 accomplished labeling without the conduct of clinical trials. SDF were exclusively used in 26.3%, 44.9%, 85.1%, and 94.1% of studies in children < 2 yr, 2-5 yr, 6-12 yr and > 12 yr, respectively. Of trials employing an oral PF formulation, 85% were associated with a marketed PF product at labeling. Marketed oral PF formulations were also associated with 8% of cases where studies relied exclusively on a s SDF. Nearly all non-enteral drug studies were supported by existing commercial formulations with only investigational inhalation formulations making their way to market. Legislative provisions enacted to incentivize pediatric drug development incompletely extend to pediatric reformulation efforts despite the associated financial gains.
Pediatric acute lymphoblastic leukemia (ALL) has cure rates exceeding 80%, yet approximately 20% of patients experience relapse, for whom treatment remains challenging. The biological and clinical heterogeneity of ALL complicates therapeutic decision-making, especially in relapse. A functional, patient-specific tool to identify effective drugs could complement current stratification approaches and potentially optimize therapy selection. We developed ELDA (Ex vivo Leukemia Drug Advisor), a novel drug screening platform based on time-lapse bright-field microscopy. Primary ALL cells were co-cultured with human bone marrow stromal cells in a three-dimensional collagen matrix, replicating a physiologically relevant microenvironment. Candidate drugs were added, and wells were imaged every 30 min for 96 h. A custom image analysis algorithm quantified viable cells by detecting subtle cell membrane movements, enabling real-time monitoring of treatment response. ELDA's results demonstrated strong concordance with established cytotoxicity assays, including MTT and Calcein-AM, validating its performance in vitro. Drug profiling of 25 pediatric ALL samples against a panel of 50 clinically relevant and experimental agents revealed distinct sensitivity and resistance patterns for each patient. Notably, heterogeneity was observed even among cases sharing the same genetic alterations, underscoring the limitations of genotype-based therapeutic predictions alone. Drugs with similar mechanisms of action exhibited correlated activity profiles, confirming the biological consistency of the assay. Importantly, ELDA-predicted differences in sensitivity to dexamethasone and vincristine were validated in vivo, further supporting its translational relevance. ELDA is a standardized and validated ex vivo drug screening methodology capable of generating individualized drug response profiles for pediatric ALL. Beyond its investigational potential in precision oncology, ELDA offers a platform for preclinical evaluation of novel agents and drug combinations.
Development of de novo therapeutic agents is a complex, costly, and a high-risk process, whereas repurposing approved and investigational drugs for novel targets offers a more efficient and cost-effective strategy, likely yielding higher success rates. This approach demonstrated its effectiveness during SARS-CoV-2 pandemic, when existing drugs were repurposed to combat the virus. Originally pivotal in developing antiviral treatments against HIV and HCV, viral protease inhibitors represent a structurally privileged class of compounds capable of targeting difficult and non-classical protein sites. They have demonstrated promising biological activity against diverse alternative targets, including fungal pathogens, multidrug-resistant bacteria, and cancer, making them prime candidates for repurposing. This mini-review highlights the unique structural and physicochemical properties of approved HCV and HIV viral protease inhibitors that enable their repurposing for the development of new therapeutic agents.
The demand for diagnosis and treatment of inherited bleeding disorders, particularly hemophilia, is increasing in China. In recent years, significant progress has been made in the country regarding the development and application of related therapeutics and the construction of the Chinese healthcare delivery system with attention to more efficient, cost-effective and convenient healthcare access to the population in both the remote/rural and urban areas. This article aims to systematically review the current therapeutic landscape of inherited bleeding disorders in China, elucidate the developmental pipeline of investigational domestic novel drugs, and discuss the establishment of a tiered healthcare system for hemophilia in China in line with the developing national healthcare delivery system. Attention to research and development in China have resulted in increased therapeutic product manufacturing capacity, and China is progressively establishing a domestic supply system for therapeutics ranging from basic replacement therapies to advanced treatments including gene therapy for inherited bleeding disorders. Concurrently, the ongoing development of the tiered healthcare system is expected to optimize the allocation of medical resources and enhance the standardization of diagnosis and treatment nationwide. In the future, the successful development of domestic innovative drugs, combined with an efficient and cost-effective healthcare delivery system, will lay a solid foundation for improving treatment outcomes and the quality of life for patients in China.
Chronic liver diseases are associated with changes in gut microbiome composition and function. Early data suggest that fecal microbiota transplantation (FMT) may treat several chronic liver diseases, especially cirrhosis, hepatic encephalopathy, and alcohol-associated liver disease. Well-powered and multisite studies are needed to better understand which indications and subpopulations hold promise for FMT. At present, there is variability in the screening, processing, and administration of FMT. Some of this variability is inherent to the nature of FMT, but some of the variability could be standardized to optimize safety and efficacy. Ultimately, we may find that narrowed and donor-independent microbiome therapeutics are superior tools to provide a consistently effective result in chronic liver disease. Regulation of FMT for chronic liver disease indications in the United States will continue to require the rigid regulatory framework of other drugs, requiring an Investigational New Drug (IND) application.
Autophagy is a cellular degradation process that plays a critical role in maintaining homeostasis and preventing stress-induced damage, making it a promising therapeutic target for cancer and neurodegenerative diseases. In this study, we utilized mouse embryonic fibroblasts expressing GFP-labeled microtubule-associated protein 1 light chain 3, a widely used biomarker of autophagy activation, to screen 3733 clinically approved or investigational drugs using a high-throughput and high-content screening platform. From the primary screening, 117 compounds were identified as potential autophagy inducers. Subsequent confirmation studies narrowed this group to 5 previously uncharacterized autophagy-inducing candidates for further investigation. Follow-up studies assessed the mechanisms underlying autophagy modulation by these compounds, with a focus on key pathways such as mechanistic target of rapamycin inhibition, endoplasmic reticulum stress activation, and p53 activation. To further explore their therapeutic potential in cancer, we conducted an angiogenesis inhibition assay. This study successfully identified several autophagy inducers that may be repurposed for the treatment of cancer, highlighting their potential for future therapeutic development. SIGNIFICANT STATEMENT: This study identifies novel autophagy inducers from high-throughput screening of approved and investigational drugs. The findings highlight key pathways such as mechanistic target of rapamycin inhibition and endoplasmic reticulum stress activation, and demonstrate the ability of these compounds to inhibit angiogenesis, suggesting their potential for repurposing in cancer therapy.
Exposure of a vital dental pulp following deep caries removal, accidental restorative procedures or trauma can severely affect the dentin-pulp complex in adult permanent teeth. To preserve a biologically functional healthy pulp, promote dentin repair, and minimize invasive and costly procedures, direct pulp capping is commonly used in vital pulp therapies. Despite its well-accepted therapeutic value, current pulp capping inorganic hydraulic calcium-silicate cements like mineral trioxide aggregate show limited targeted bioactive effects. Therefore, repurposing clinically approved drugs or investigational small bioactive agents targeting intracellular signaling pathways relevant to reparative dentinogenesis may translate into novel therapeutic approaches for dentin repair. Here, we review studies published over the past decade that explore two agents for potential repurposing in dentin repair: tideglusib, a glycogen synthase kinase‑3 inhibitor, and metformin, a widely used anti‑diabetic biguanide DESIGN: PubMed was used as the single, web-based search engine and database. Only studies using dental pulp stem cells in which the drugs were investigated as single agents were included. While incorporated into different biomaterial formulations, both tideglusib and metformin, trigger significant upregulation of odontoblastic differentiation markers and mineral synthesis in dental pulp stem cells in vitro. Tideglusib has also been shown to significantly enhance reparative dentinogenesis in experimental animal models. Leveraging drug repurposing for dentin repair underscores the significance of translating into dentistry knowledge gained from basic, pre-clinical and clinical research in other medical conditions, laying the groundwork for cost-effective therapeutic strategies and improved outcomes in regenerative dental medicine.