Development of novel focal adhesion kinase (FAK) inhibitors for targeting cancer: Structural insights and therapeutic potential.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase frequently overexpressed in various cancer cells, facilitating tumor growth through the regulation of cell adhesion, migration, and proliferation. Consequently, targeting FAK is considered a promising anti-tumor strategy, particularly for invasive cancers. Numerous potent small-molecule inhibitors have progressed to clinical trials. Among these, Defactinib is under evaluation for regulatory approval as a treatment for ovarian serous tumors. Furthermore, novel FAK inhibitors, including PROTACs, have emerged as key research focuses, anticipated to overcome the limitations of traditional inhibitors. In this Perspective, we highlight the protein structure, biological functions, relevant signaling pathways, and associations of FAK with cancer development. We also analyze the clinical status of FAK inhibitors, paying special attention to the various classes of FAK inhibitors, with detailed analyses of their chemical structures, structure-activity relationships (SARs), bioactivity profiles, selectivity profiles, and therapeutic potentials.

Targeting HSP90 for Cancer Therapy: Current Progress and Emerging Prospects.

Heat shock protein 90 (HSP90), a highly conserved member of the heat shock protein family, regulates various proteins and signaling pathways involved in cancer, making it a promising target for cancer therapy. Traditional HSP90 inhibitors have demonstrated significant antitumor potential in preclinical trials, with over 20 compounds advancing to clinical trials and showing promising results. However, the limited clinical efficacy and shared toxicity of these inhibitors restrict their further clinical use. Encouragingly, developing novel inhibitors using conventional medicinal chemistry approaches─such as selective inhibitors, dual inhibitors, protein-protein interaction inhibitors, and proteolysis-targeting chimeras─is expected to address these challenges. Notably, the selective inhibitor TAS-116 has already been successfully marketed. In this Perspective, we summarize the structure, biological functions, and roles of HSP90 in cancer, analyze the clinical status of HSP90 inhibitors, and highlight the latest advancements in novel strategies, offering insights into their future development.

An update on small molecule compounds targeting synthetic lethality for cancer therapy.

Targeting cancer-specific vulnerabilities through synthetic lethality (SL) is an emerging paradigm in precision oncology. A SL strategy based on PARP inhibitors has demonstrated clinical efficacy. Advances in DNA damage response (DDR) uncover novel SL gene pairs. Beyond BRCA-PARP, emerging SL targets like ATR, ATM, DNA-PK, CHK1, WEE1, CDK12, RAD51, and RAD52 show clinical promise. Selective and bioavailable small molecule inhibitors have been developed to induce SL, but optimization for potency, specificity, and drug-like properties remains challenging. This article illuminated recent progress in the field of medicinal chemistry centered on the rational design of agents capable of eliciting SL specifically in neoplastic cells. It is envisioned that innovative strategies harnessing SL for small molecule design may unlock novel prospects for targeted cancer therapeutics going forward.

Small Molecular Inhibitors That Target ATM for Drug Discovery: Current Research and Potential Prospective.

The protein kinase ataxia telangiectasia mutated (ATM) is a constituent of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, exerting a pivotal influence on diverse cellular processes, notably the signaling of double-strand DNA breaks (DSB) and stress response. The dysregulation of ATM is implicated in the pathogenesis of cancer and other diseases such as neurodegeneration. Hence, ATM is deemed a promising candidate for potential therapeutic interventions across a spectrum of diseases. Presently, while ATM small molecule inhibitors are not commercially available, various selective inhibitors have progressed to the clinical research phase. Specifically, AZD1390, WSD0628, SYH2051, and ZN-B-2262 are under investigation in clinical studies pertaining to glioblastoma multiforme and advanced solid tumors, respectively. In this Perspective, we encapsulate the structure, biological functions, and disease relevance of ATM. Subsequently, we concentrate on the design concepts and structure-activity relationships (SAR) of ATM inhibitors, delineating potential avenues for the development of more efficacious ATM-targeted inhibitors.

Unveiling the bioinformatic genes and their involved regulatory mechanisms in type 2 diabetes combined with osteoarthritis.

Background: Type 2 Diabetes Mellitus (T2D) and Osteoarthritis (OA) are both prevalent diseases that significantly impact the health of patients. Increasing evidence suggests that there is a big correlation between T2D and OA, but the molecular mechanisms remain elusive. The aims of this study are to investigate the shared biomarkers and potential molecular mechanisms in T2D combined with OA. Methods: T2D and OA-related differentially expressed genes (DEGs) were identified via bioinformatic analysis on Gene Expression Omnibus (GEO) datasets GSE26168 and GSE114007 respectively. Subsequently, extensive target prediction and network analysis were finished with Gene Ontology (GO), protein-protein interaction (PPI), and pathway enrichment with DEGs. The transcription factors (TFs) and miRNAs coupled in co-expressed DEGs involved in T2D and OA were predicted as well. The key genes expressed both in the clinical tissues of T2D and OA were detected with western blot and qRT-PCR assay. Finally, the most promising candidate compounds were predicted with the Drug-Gene Interaction Database (DGIdb) and molecular docking. Results: In this study, 209 shared DEGs between T2D and OA were identified. Functional analysis disclosed that these DEGs are predominantly related to ossification, regulation of leukocyte migration, extracellular matrix (ECM) structural constituents, PI3K/AKT, and Wnt signaling pathways. Further analysis via Protein-Protein Interaction (PPI) analysis and validation with external datasets emphasized MMP9 and ANGPTL4 as crucial genes in both T2D and OA. Our findings were validated through qRT-PCR and Western blot analyses, which indicated high expression levels of these pivotal genes in T2D, OA, and T2D combined with OA cases. Additionally, the analysis of Transcription Factors (TFs)-miRNA interactions identified 7 TFs and one miRNA that jointly regulate these important genes. The Receiver Operating characteristic (ROC) analysis demonstrated the significant diagnostic potential of MMP9 and ANGPTL4.Moreover, we identified raloxifene, ezetimibe, and S-3304 as promising agents for patients with both T2D and OA. Conclusion: This study uncovers the shared signaling pathways, biomarkers, potential therapeutics, and diagnostic models for individuals suffering from both T2D and OA. These findings not only present novel perspectives on the complex interplay between T2D and OA but also hold significant promise for improving the clinical management and prognosis of patients with this concurrent condition.

Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies.

Alzheimer's disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate and diverse, stemming from a combination of factors such as aging, genetics, and environment. Our current understanding of AD pathologies involves various hypotheses, such as the cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, and abnormal autophagy. Nonetheless, unraveling the interplay among these pathological aspects and pinpointing the primary initiators of AD require further elucidation and validation. In the past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available drugs primarily offer symptomatic relief and often accompanied by undesirable side effects. However, recent approvals of aducanumab (1) and lecanemab (2) by the Food and Drug Administration (FDA) present the potential in disrease-modifying effects. Nevertheless, the long-term efficacy and safety of these drugs need further validation. Consequently, the quest for safer and more effective AD drugs persists as a formidable and pressing task. This review discusses the current understanding of AD pathogenesis, advances in diagnostic biomarkers, the latest updates of clinical trials, and emerging technologies for AD drug development. We highlight recent progress in the discovery of selective inhibitors, dual-target inhibitors, allosteric modulators, covalent inhibitors, proteolysis-targeting chimeras (PROTACs), and protein-protein interaction (PPI) modulators. Our goal is to provide insights into the prospective development and clinical application of novel AD drugs.

Efficacy of auxetic lattice structured shoe sole in advancing footwear comfort-From the perspective of plantar pressure and contact area.

Introduction: Designing footwear for comfort is vital for preventing foot injuries and promoting foot health. This study explores the impact of auxetic structured shoe soles on plantar biomechanics and comfort, motivated by the integration of 3D printing in footwear production and the superior mechanical properties of auxetic designs. The shoe sole designs proposed in this study are based on a three-dimensional re-entrant auxetic lattice structure, orthogonally composed of re-entrant hexagonal honeycombs with internal angles less than 90 degrees. Materials fabricated using this lattice structure exhibit the characteristic of a negative Poisson's ratio, displaying lateral expansion under tension and densification under compression. Methods: The study conducted a comparative experiment among three different lattice structured (auxetic 60°, auxetic 75° and non-auxetic 90°) thermoplastic polyurethane (TPU) shoe soles and conventional polyurethane (PU) shoe sole through pedobarographic measurements and comfort rating under walking and running conditions. The study obtained peak plantar pressures (PPPs) and contact area across seven plantar regions of each shoe sole and analyzed the correlation between these biomechanical parameters and subjective comfort. Results: Compared to non-auxetic shoe soles, auxetic structured shoe soles reduced PPPs across various foot regions and increased contact area. The Auxetic 60°, which had the highest comfort ratings, significantly lowered peak pressures and increased contact area compared to PU shoe sole. Correlation analysis showed that peak pressures in specific foot regions (hallux, second metatarsal head, and hindfoot when walking; second metatarsal head, third to fifth metatarsal head, midfoot, and hindfoot when running) were related to comfort. Furthermore, the contact area in all foot regions was significantly associated with comfort, regardless of the motion states. Conclusion: The pressure-relief performance and conformability of the auxetic lattice structure in the shoe sole contribute to enhancing footwear comfort. The insights provided guide designers in developing footwear focused on foot health and comfort using auxetic structures.

Development and therapeutic perspectives of CXCR4 antagonists for disease therapy.

Chemokine receptor 4 (CXCR4) is a subtype receptor protein of the GPCR family with a seven-transmembrane structure widely distributed in human tissues. CXCR4 is involved in diseases (e.g., HIV-1 infection), cancer proliferation and metastasis, inflammation signaling pathways, and leukemia, making it a promising drug target. Clinical trials on CXCR4 antagonists mainly focused on peptides and antibodies, with a few small molecule compounds, such as AMD11070 (2) and MSX-122 (3), showing promise in cancer treatment. This perspective discusses the structure-activity relationship (SAR) of CXCR4 and its role in diseases, mainly focusing on the SAR of CXCR4 antagonists. It also explores the standard structural features and target interactions of CXCR4 binding in different disease categories. Furthermore, it investigates various modification strategies to propose potential improvements in the effectiveness of CXCR4 drugs.

Perspectives and challenges in developing small molecules targeting purine nucleoside phosphorylase.

As a cytosolic enzyme involved in the purine salvage pathway metabolism, purine nucleoside phosphorylase (PNP) plays an important role in a variety of cellular functions but also in immune system, including cell growth, apoptosis and cancer development and progression. Based on its T-cell targeting profile, PNP is a potential target for the treatment of some malignant T-cell proliferative cancers including lymphoma and leukemia, and some specific immunological diseases. Numerous small-molecule PNP inhibitors have been developed so far. However, only Peldesine, Forodesine and Ulodesine have entered clinical trials and exhibited some potential for the treatment of T-cell leukemia and gout. The most recent direction in PNP inhibitor development has been focused on PNP small-molecule inhibitors with better potency, selectivity, and pharmacokinetic property. In this perspective, considering the structure, biological functions, and disease relevance of PNP, we highlight the recent research progress in PNP small-molecule inhibitor development and discuss prospective strategies for designing additional PNP therapeutic agents.

Recent discovery and development of AXL inhibitors as antitumor agents.

AXL, a receptor tyrosine kinase (RTK), plays a pivotal role in various cellular functions. It is primarily involved in processes such as epithelial-mesenchymal transition (EMT) in tumor cells, angiogenesis, apoptosis, immune regulation, and chemotherapy resistance mechanisms. Therefore, targeting AXL is a promising therapeutic approach for the treatment of cancer. AXL inhibitors that have entered clinical trials, such as BGB324(1), have shown promising efficacy in the treatment of melanoma and non-small cell lung cancer. Additionally, novel AXL-targeted drugs, such as AXL degraders, offer a potential solution to overcome the limitations of traditional small-molecule AXL inhibitors targeting single pathways. We provide an overview of the structure and biological functions of AXL, discusses its correlation with various cancers, and critically analyzes the structure-activity relationship of AXL small-molecule inhibitors in cellular contexts. Additionally, we summarize multiple research and development strategies, offering insights for the future development of innovative AXL inhibitors.

Development and therapeutic implications of small molecular inhibitors that target calcium-related channels in tumor treatment.

Calcium ion dysregulation exerts profound effects on various physiological activities such as tumor proliferation, migration, and drug resistance. Calcium-related channels play a regulatory role in maintaining calcium ion homeostasis, with most channels being highly expressed in tumor cells. Additionally, these channels serve as potential drug targets for the development of antitumor medications. In this review, we first discuss the current research status of these pathways, examining how they modulate various tumor functions such as epithelial-mesenchymal transition (EMT), metabolism, and drug resistance. Simultaneously, we summarize the recent progress in the study of novel small-molecule drugs over the past 5 years and their current status.

Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications.

CDK9 is a cyclin-dependent kinase that plays pivotal roles in multiple cellular functions including gene transcription, cell cycle regulation, DNA damage repair, and cellular differentiation. Targeting CDK9 is considered an attractive strategy for antitumor therapy, especially for leukemia and lymphoma. Several potent small molecule inhibitors, exemplified by TG02 (4), have progressed to clinical trials. However, many of them face challenges such as low clinical efficacy and multiple adverse reactions and may necessitate the exploration of novel strategies to lead to success in the clinic. In this perspective, we present a comprehensive overview of the structural characteristics, biological functions, and preclinical status of CDK9 inhibitors. Our focus extends to various types of inhibitors, including pan-inhibitors, selective inhibitors, dual-target inhibitors, degraders, PPI inhibitors, and natural products. The discussion encompasses chemical structures, structure-activity relationships (SARs), biological activities, selectivity, and therapeutic potential, providing detailed insight into the diverse landscape of CDK9 inhibitors.

Current advances and development strategies of targeting son of sevenless 1 (SOS1) in drug discovery.

The Son of Sevenless 1 (SOS1) guanine nucleotide exchange factor, prevalent across eukaryotic species, plays a pivotal role in facilitating the attachment of RAS protein to GTP, thereby regulating the activation of intracellular RAS proteins. This regulation is part of a feedback mechanism involving SOS1, which allows both activators and inhibitors of SOS1 to exert control over downstream signaling pathways, demonstrating potential anti-tumor effects. Predominantly, small molecule modulators that target SOS1 focus on a hydrophobic pocket within the CDC25 protein domain. The effectiveness of these modulators largely depends on their ability to interact with specific amino acids, notably Phe890 and Tyr884. This interaction is crucial for influencing the protein-protein interaction (PPI) between RAS and the catalytic domain of SOS1. Currently, most small molecule modulators targeting SOS1 are in the preclinical research phase, with a few advancing to clinical trials. This progression raises safety concerns, making the assurance of drug safety a primary consideration alongside the enhancement of efficacy in the development of SOS1 modulators. This review encapsulates recent advancements in the chemical categorization of SOS1 inhibitors and activators. It delves into the evolution of small molecule modulation targeting SOS1 and offers perspectives on the design of future generations of selective SOS1 small molecule modulators.

Insight into small-molecule inhibitors targeting extracellular nucleotide pyrophosphatase/phosphodiesterase1 for potential multiple human diseases.

Extracellular nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) has been identified as a type II transmembrane glycoprotein. It plays a crucial role in various biological processes, such as bone mineralization, cancer cell proliferation, and immune regulation. Consequently, ENPP1 has garnered attention as a promising target for pharmacological interventions. Despite its potential, the development of clinical-stage ENPP1 inhibitors for solid tumors, diabetes, and silent rickets remains limited. However, there are encouraging findings from preclinical trials involving small molecules exhibiting favorable therapeutic effects and safety profiles. This perspective aims to shed light on the structural properties, biological functions and the relationship between ENPP1 and diseases. Additionally, it focuses on the structure-activity relationship of ENPP1 inhibitors, with the intention of guiding the future development of new and effective ENPP1 inhibitors.

Research progress of DDR1 inhibitors in the treatment of multiple human diseases.

Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase (RTK) and plays pivotal roles in regulating cellular functions such as proliferation, differentiation, invasion, migration, and matrix remodeling. DDR1 is involved in the occurrence and progression of many human diseases, including cancer, fibrosis, and inflammation. Therefore, DDR1 represents a highly promising therapeutic target. Although no selective small-molecule inhibitors have reached clinical trials to date, many molecules have shown therapeutic effects in preclinical studies. For example, BK40143 has demonstrated significant promise in the therapy of neurodegenerative diseases. In this context, our perspective aims to provide an in-depth exploration of DDR1, encompassing its structure characteristics, biological functions, and disease relevance. Furthermore, we emphasize the importance of understanding the structure-activity relationship of DDR1 inhibitors and highlight the unique advantages of dual-target or multitarget inhibitors. We anticipate offering valuable insights into the development of more efficacious DDR1-targeted drugs.

Comprehensive Insights that Targeting PIM for Cancer Therapy: Prospects and Obstacles.

Proviral integration sitea for Moloney-murine leukemia virus (PIM) kinases are a family of highly conserved serine/tyrosine kinases consisting of three members, PIM-1, PIM-2, and PIM-3. These kinases regulate a wide range of substrates through phosphorylation and affect key cellular processes such as transcription, translation, proliferation, apoptosis, and energy metabolism. Several PIM inhibitors are currently undergoing clinical trials, such as a phase I clinical trial of Uzanserti (5) for the treatment of relapsed diffuse large B-cell lymphoma that has been completed. The current focus encompasses the structural and biological characterization of PIM, ongoing research progress on small-molecule inhibitors undergoing clinical trials, and evaluation analysis of persisting challenges in this field. Additionally, the design and discovery of small-molecule inhibitors targeting PIM in recent years have been explored, with a particular emphasis on medicinal chemistry, aiming to provide valuable insights for the future development of PIM inhibitors.

GLS and GOT2 as prognostic biomarkers associated with dendritic cell and immunotherapy response in breast cancer.

Breast cancer is the females' most common cancer. Targeting the immune microenvironment is a new and promising treatment method for breast cancer. Nevertheless, only a small section of patients can profit by immunotherapy, and improving the ability to accurately predict the potential for immunotherapy response is still awaiting further exploration. In this study, we found that the key factors of glutamine metabolism, glutaminase 1 (GLS) and mitochondrial aspartate transaminase (GOT2), showed opposite expression patterns in breast cancer samples. Based on the expression level of GLS and GOT2, we divided the breast cancer samples into two clusters: Cluster 2 showed GLS expressed higher and GOT2 expressed lower, whereas Cluster 1 showed GOT2 expressed higher and GLS expressed lower. GSEA showed that the clusters were related to pathways of immunity. Further analysis showed that Cluster 2 was positively associated with immunity infiltration. Through WGCNA, we identified a module strongly correlated with glutamine metabolism and immunity and identified 11 dendritic cell-associated genes involved in dendritic cell development, maturation, activation and other functions. In addition, Cluster 2 also showed higher immune checkpoint gene expression, which suggest the Cluster 2 had even better response to immunotherapy. The validation dataset could also be clustered into two groups. Cluster 2 (GLS expressed higher and GOT2 expressed lower) of the validation dataset was also positively associated with dendritic cells and a better immunotherapy response. Thus, these data indicate that GLS and GOT2 are prognostic biomarkers which closely related to dendritic cells and better reacted to immunotherapy in breast cancer.

Advancements in dual-target inhibitors of PI3K for tumor therapy: Clinical progress, development strategies, prospects.

Phosphoinositide 3-kinases (PI3Ks) modify lipids by the phosphorylation of inositol phospholipids at the 3'-OH position, thereby participating in signal transduction and exerting effects on various physiological processes such as cell growth, metabolism, and organism development. PI3K activation also drives cancer cell growth, survival, and metabolism, with genetic dysregulation of this pathway observed in diverse human cancers. Therefore, this target is considered a promising potential therapeutic target for various types of cancer. Currently, several selective PI3K inhibitors and one dual-target PI3K inhibitor have been approved and launched on the market. However, the majority of these inhibitors have faced revocation or voluntary withdrawal of indications due to concerns regarding their adverse effects. This article provides a comprehensive review of the structure and biological functions, and clinical status of PI3K inhibitors, with a specific emphasis on the development strategies and structure-activity relationships of dual-target PI3K inhibitors. The findings offer valuable insights and future directions for the development of highly promising dual-target drugs targeting PI3K.

Emerging opportunities to treat idiopathic pulmonary fibrosis: Design, discovery, and optimizations of small-molecule drugs targeting fibrogenic pathways.

Idiopathic pulmonary fibrosis (IPF) is the most common fibrotic form of idiopathic diffuse lung disease. Due to limited treatment options, IPF patients suffer from poor survival. About ten years ago, Pirfenidone (Shionogi, 2008; InterMune, 2011) and Nintedanib (Boehringer Ingelheim, 2014) were approved, greatly changing the direction of IPF drug design. However, limited efficacy and side effects indicate that neither can reverse the process of IPF. With insights into the occurrence of IPF, novel targets and agents have been proposed, which have fundamentally changed the treatment of IPF. With the next-generation agents, targeting pro-fibrotic pathways in the epithelial-injury model offers a promising approach. Besides, several next-generation IPF drugs have entered phase II/III clinical trials with encouraging results. Due to the rising IPF treatment requirements, there is an urgent need to completely summarize the mechanisms, targets, problems, and drug design strategies over the past ten years. In this review, we summarize known mechanisms, target types, drug design, and novel technologies of IPF drug discovery, aiming to provide insights into the future development and clinical application of next-generation IPF drugs.

Wheat cis-zeatin-O-glucosyltransferase cZOGT1 interacts with the Ca2+-dependent lipid binding protein TaZIP to regulate senescence.

Premature senescence is an important factor affecting wheat yield and quality. Wheat yield can be increased by delaying senescence and prolonging the effective photosynthetic time. Previously, we found that the cis-zeatin-O-glucosyltransferase (cZOGT1) gene plays an important role in the stay-green wheat phenotype. In this study, cZOGT1-overexpressing lines exhibited a delayed senescence phenotype, despite a significant reduction in the total cytokinin content. Further, we found that cZOGT1 interacted with the Ca2+-dependent lipid binding protein TaZIP (cZOGT1-interacting protein), and that a high level of cZOGT1 expression led to the suppression of TaZIP expression, which in turn, reduced abscisic acid (ABA) content. The synergistic reduction in cytokinins and ABA levels eventually caused the stay-green phenotype in cZOGT1-overexpressing lines. This study provides a new theoretical basis to explain the mechanism underlying the wheat stay-green phenotype and provides a genetic resource for wheat molecular-design breeding.