Search Results (253)

Despite a thorough understanding of the structure of human papillomavirus (HPV) and its genotypic variations (high-risk and low-risk variants), the mechanisms underlying HPV-induced cervical cancer (CC) pathogenesis and the molecular signatures of drug resistance remain to be fully understood. Accumulating evidence has shown the involvement of kinase targets in the induction of drug resistance in high-risk (HR) HPV-CC. Molecularly, the genome of high-risk HPV is reported to control the expression of host kinases. In particular, Aurora kinases A, B, and C (ARKA, ARKB, and ARKC), phosphotidylinositol–trisphosphate kinase (PI3K)-Akt, and Glycogen synthase kinase3-α/β (GSK3 α/β) promote the transformation of infected cells, and also enhance the resistance of cells to various chemotherapeutic agents such as nelfinavir and cisplatin. However, the precise mechanisms through which HPV activates these kinases are yet to be fully elucidated. Furthermore, there is still ambiguity surrounding whether targeting HPV-induced kinases along with HPV-targeted therapies (such as phytopharmaceuticals and PROTAC/CRISPR-CAS-based systems) synergistically inhibit cervical tumor growth. Given the critical role of kinases in the pathogenesis and treatment of CC, a comprehensive review of current evidence is warranted. This review aims to provide key insights into the mechanisms of HPV-induced CC development, the involvement of kinases in drug resistance induction, and the rationale for combination therapies to improve clinical outcomes. Full article

Alzheimer’s disease (AD) involves a constellation of molecular processes that extend well beyond amyloid-β (Aβ) accumulation. Recent anti-amyloid antibodies provide limited clinical benefits, highlighting the need for additional strategies due to their modest efficacy and safety concerns. Increasing proteomic evidence reveals that proteins such as midkine (MDK), pleiotrophin (PTN) and clusterin (CLU) accumulate within amyloid plaques and may shape disease progression, although their precise contributions—protective, pathogenic, or both—remain unknown. In this Perspective, we examine how emerging targeted protein degradation (TPD) technologies, including Proteolysis-Targeting Chimeras (PROTACs), Lysosome-Targeting Chimeras (LYTACs) and molecular glues (MGs), could provide a means to selectively eliminate these co-aggregating proteins. We also discuss advances in degrader design, artificial intelligence (AI)-assisted screening, and strategies aimed at enhancing Central Nervous System (CNS) delivery. We finally outline how integrating TPD modalities with antibody-based and multi-target therapeutic approaches may promote more effective, systems-level interventions for AD. Full article

Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are becoming more prevalent and still lack effective disease-modifying therapies (DMTs). However, translational efficiency remains critically low. For example, a ClinicalTrials.gov analysis of AD programs (2002–2012) estimated ~99.6% attrition, while PD programs (1999–2019) achieved an overall success rate of ~14.9%. In vitro platforms are assessed, ranging from immortalized neuronal lines and primary cultures to human-induced pluripotent stem cell (iPSC)-derived neurons/glia, neuron–glia co-cultures (including neuroinflammation paradigms), 3D spheroids, organoids, and blood–brain barrier (BBB)-on-chip systems. Complementary in vivo toxin, pharmacological, and genetic models are discussed for systems-level validation and central nervous system (CNS) exposure realism. The therapeutic synthesis focuses on AD, covering symptomatic drugs, anti-amyloid immunotherapies, tau-directed approaches, and repurposed drug classes that target metabolism, neuroinflammation, and network dysfunction. This review links experimental models to translational decision-making, focusing primarily on AD and providing a brief comparative context from other NDDs. It also covers emerging targeted protein degradation (PROTACs). Key priorities include neuroimmune/neurovascular human models, biomarker-anchored adaptive trials, mechanism-guided combination DMTs, and CNS PK/PD-driven development for brain-directed degraders. Full article

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) are characterized by complex pathologies with progressive neurodegeneration, protein misfolding, oxidative stress, and persistent inflammation. Recent findings indicate the pivotal involvement of epigenetic disruption, particularly aberrant histone deacetylase (HDAC) activity, in disease initiation and progression. In the current review, we systematically discuss the mechanistic function of HDACs across all classes (I, IIa, IIb, III, and IV) in neurodegenerative disease mechanisms, such as their involvement in the modulation of gene expression, mitochondrial function, proteostasis, and neuronal survival. We discuss the therapeutic potential, as well as limitations, of HDAC inhibitors (HDACis), such as pan-inhibitors and isoenzyme-selective inhibitors, and new multi-target-directed ligands with HDAC inhibition combined with acetylcholinesterase modulation, PDE modulation, MAO-B inhibition, or NMDAR modulation. Particular emphasis is placed on the development of HDAC6-selective inhibitors with enhanced brain permeability and reduced toxicity, which have shown promising preclinical efficacy in ameliorating hallmark pathologies of AD, PD, and HD. In addition, s-triazine-based scaffolds have recently emerged as promising chemotypes in HDAC inhibitor design, offering favorable pharmacokinetic profiles, metabolic stability, and the potential for dual-target modulation relevant to neurodegeneration. The review also explores the future of HDAC-targeted therapies, including PROTAC degraders, dual-inhibitor scaffolds, and sustainable, BBB-penetrant molecules. Collectively, this review underscores the importance of HDAC modulation as a multifaceted strategy in the treatment of neurodegenerative diseases and highlights the need for continued innovation in epigenetic drug design. Full article

Triple-Negative Breast Cancer (TNBC) remains the most aggressive breast cancer subtype, characterized by profound heterogeneity and a lack of effective targeted therapies. Although cytotoxic chemotherapy is the standard of care, the rapid emergence of resistance driven by cancer stem cells (CSCs), metabolic plasticity, and the tumor microenvironment limits long-term survival. This review highlights the paradigm shift in TNBC treatment from 2021 to 2025, moving beyond broad cytotoxicity to precision medicine. We first examine the limitations of earlier targeted therapies, such as PI3K/AKT/mTOR inhibitors, which failed due to compensatory feedback loops and toxicity. We then discuss emerging synthetic lethality strategies targeting the G2/M checkpoint (WEE1, ATR) and mitotic kinases (PLK1, TTK) to exploit genomic instability in TP53-mutant tumors. Furthermore, we explore how novel modalities like PROTACs and Antibody–Drug Conjugates (ADCs) are unlocking the “undrugged kinome,” including targets like TNIK, PTK7, and PAK4, which were previously inaccessible. Finally, we propose that future success lies in combinatorial strategies integrating these next-generation kinase inhibitors with ADCs and immunotherapies to dismantle therapeutic resistance. Full article

The mitogen-activated protein kinase (MAPK) signaling cascade is fundamental in regulating cellular proliferation and differentiation, cell survival and cell death via apoptosis. Disruption of the MAPK signaling cascade at any point can lead to the evasion of apoptosis and unchecked cell growth and proliferation, leading to oncogenesis. This narrative review describes MAPK pathway dysregulation, its therapeutic targets, and resistance mechanisms. The therapeutic targeting of the MAPK pathway is complex due to the dual context-dependent roles of several kinases in the signaling cascade. Despite the therapeutic effectiveness of MAPK inhibitors, cancer cells develop chemoresistance that needs to be targeted via bypassing (c-Jun N-terminal kinases) JNK, protein kinase AKT and (mammalian target of rapamycin) mTOR signaling cascades, pairing MAPK inhibitors with multiple immune agents and targeting the MAPK pathway downstream of (extracellular signal-regulated kinase) ERK to prevent its reactivation mechanisms using combination therapies, downstream signaling regulators and (Proteolysis Targeting Chimeras) PROTACs. Additionally, MAPK-mediated regulation of ferroptosis is a novel oncological therapeutic targeting strategy for controlling tumor progression. The inhibition of the RAF/MAPK pathway results in alteration of several key regulators of ferroptosis, including SLCA11, GSH, GPX4 and NCO4A, hence affecting lipid cellular iron concentration and lipid peroxidation. Emerging therapies targeting the MAPK pathway should be designed considering crosstalk, compensatory signaling mechanism activation, the role of ferroptosis and the impact of the tumor microenvironment. Full article

Proteolysis-targeting chimeras (PROTACs) have emerged as a revolutionary therapeutic modality that enables degradation of therapeutically relevant proteins through the protein disposal machinery, the ubiquitin-proteasome system (UPS). Unlike traditional small-molecule inhibitors, PROTACs harness bifunctional molecules to induce targeted protein degradation, offering advantages such as increased specificity, catalytic activity, and the potential to address previously undruggable targets. Since their conception 20 years ago, PROTACs have made significant strides in target protein degradation (TPD), and today, PROTACs are on the verge of their first clinical approval. This review presents a detailed overview of PROTAC targets, clinical development progress, and the design and detailed synthesis of degrader molecules that have advanced to clinical trials. Full article

Background: In recent years, compounds known as Proteolysis Targeted Chimeras (PROTACs) have revitalized the field of bioactive molecule design. These compounds promote proteolysis of therapeutic targets by recruiting them to ubiquitin ligases. One of the most commonly used classes of compounds in the synthesis of PROTACs are immunomodulatory imides (IMiDs), such as thalidomide (TLD), which interact with the E3 ligase CRL4^CRBN via the CULT domain of the cereblon protein (CRBN). This domain has been identified in proteins across various phylogenetic groups, including trypanosomatids, leading to the hypothesis that IMiD-derived PROTACs should be active in these organisms. Methods: The trypanocidal activity of the PROTAC dBET1 and its separated components (JQ1 and TLD) were assayed using a T. cruzi strain expressing β-glalactosidase. Potential CRL4-E3L complexes from humans and trypanosomatids were assembled in silico with MultimerMapper. The IMiD-binding site of HsCRBN and its trypanosomatid homologs were analyzed using molecular dynamics and docking simulations. Results: We demonstrate that the compound dBET1 does not function as a PROTAC in Trypanosoma cruzi. In silico structural analysis of CRL4-E3L complex orthologs revealed that the trypanosomal CULT-containing protein is not part of such a complex. Molecular dynamics simulations showed that the pocket of this CULT domain is smaller than that of mammalian CRBN and cannot accommodate IMiDs within. Conclusions: We underscore the importance of functional and structural validation in drug discovery, particularly when extrapolating mechanisms between evolutionarily distant species. While PROTACs hold promise in human therapeutics, our work advocates for re-evaluating the rationale behind thalidomide-based PROTACs in trypanosomatid research. Full article

Background: High expression of nucleolin (NCL) on the surface of tumor cells is closely associated with disease progression and poor prognosis. The aptamer–PROTAC conjugate (APC) technology provides a novel molecular design strategy for the targeted degradation of NCL. Methods: Based on the principles of PROTAC technology and chemical modification techniques, in this study, a series of AS1411-lenalidomide chimeras featuring different linker structures were designed and synthesized for the specific purpose of targeted degradation of NCL. Four AS1411-PROTACs (C1–C4) were successfully constructed via a click chemistry strategy, and their structures were validated. Results: In vitro experimental results showed that C4 exhibited the most optimal activity, significantly downregulating NCL expression and inhibiting the proliferation of breast cancer cells (MCF-7). Notably, the activity of C4 remained unaltered regardless of the annealing process. Mechanistic studies demonstrated that C4 induced NCL degradation through the ubiquitin–proteasome pathway while also promoting apoptosis and cell cycle arrest. In a nude mouse tumor model, C4 displayed potent antitumor efficacy, with no discernible signs of obvious systemic toxicity. Conclusions: This study provides compelling evidence demonstrating that C4 is a highly promising anticancer compound. It also provides important evidence for the development of novel nucleic acid aptamer–PROTAC conjugate drugs for more clinical applications. Full article

Alzheimer’s disease (AD) Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by protein aggregation, oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, leading to cognitive decline. Current therapies remain largely symptomatic, highlighting the need for multi-target therapeutic strategies. Recent advances in antioxidant natural compounds and targeted protein degradation (TPD) technologies—particularly proteolysis-targeting chimeras (PROTACs), offer complementary mechanisms for disease modification. Natural antioxidants, including flavonoids, polyphenols, terpenoids, and alkaloids, confer neuroprotection by reducing reactive oxygen species, activating Nrf2 pathways, restoring mitochondrial function, and suppressing neuroinflammation. PROTACs, in contrast, selectively degrade pathological proteins such as hyperphosphorylated tau, amyloid-β, and APP fragments through the ubiquitin–proteasome system. The integrated “Antiox-PROTAC” approach combines these modalities to simultaneously mitigate oxidative stress and eliminate neurotoxic proteins. Natural compounds may act as warheads or scaffolds in PROTAC design, retaining antioxidant activity while enabling targeted degradation. Early preclinical findings demonstrate synergistic neuroprotective potential, though translational challenges remain, including blood–brain barrier permeability, bioavailability, and delivery optimization. Future directions involve hybrid molecules, nanoparticle-based delivery, and personalized therapeutic strategies. Overall, the Antiox-PROTAC paradigm represents a next-generation, multi-modal framework with the potential to modify disease progression and enhance cognitive outcomes in Alzheimer’s disease. Full article

Proteolysis Targeting Chimeras (PROTACs) represent a transformative modality in drug discovery, enabling the selective degradation of disease-relevant proteins through the ubiquitin proteasome system. Despite their therapeutic promise, the rational design of PROTACs remains a complex and resource-intensive process, involving multiple parameters such as target and ligase compatibility, ternary complex formation, linker optimization, and degradation efficiency. Recent advances in artificial intelligence (AI) have provided new strategies to address these obstacles, ranging from structure-based modeling of ternary complexes to degradability prediction, generative linker design, and pharmacokinetic property estimation. This review aims to explore how AI can be leveraged directly or indirectly in the PROTAC development pipeline. First, we analyze existing applications of AI, such as ternary complex structure prediction, degradability prediction, linker design, and ADME prediction. We further discuss how other approaches from the related fields may be adapted to address the challenges of PROTAC discovery. Lastly, we discuss challenges that current AI models face, such as limited data, poor interpretability, and low generalizability. Taken together, overcoming these barriers will enable AI-driven strategies to accelerate PROTAC discovery and provide a more rational framework for targeted protein degrader development. Full article

The dysregulation of CK1 isoforms is linked to various types of diseases, including neurodegeneration and different types of neoplasia such as colon, pancreatic, breast, and ovarian cancer. For CK1 isoforms, a plethora of effective small molecule inhibitors are available. However, only a few degraders of CK1α and, more recently, proteolysis targeting chimeras (PROTACs) for CK1δ/CK1ε have been reported. In this study, we applied the PROTAC concept by harnessing molecular modelling to design and synthesize a series of candidate CK1δ-targeting PROTACs based on a highly specific and potent benzothiazole-based CK1δ inhibitor that we previously developed in our lab. In the present study, we established a modular synthetic platform to systematically generate a set of PROTAC degrader candidates consisting of the CK1δ-specific inhibitor scaffold, alkyl and PEG linker motifs with various lengths, and Cereblon (CRBN)-engaging pomalidomide and thalidomide derivatives as E3 ligase binders. We demonstrate that several PROTACs degrade CK1δ/ε in various cells. The most potent PROTAC P1d inhibits the phosphorylation of downstream substrates through CK1δ/ε degradation. We establish the requirement of CUL4A^CRBN and the proteasome for the P1d-mediated degradation of CK1δ/ε. Full article

Protein tyrosine phosphatases (PTPs) are prominent enzymes which play pivotal roles in the regulation of multifarious cellular functions. Dysregulations of several PTPs have well-documented implications in the pathogenesis of various human diseases, including diabetes, cancer, and neurodegenerative and inflammatory disorders. Therefore, PTPs are considered attractive targets for therapeutic intervention. However, the development of novel drugs targeting these enzymes has encountered several difficulties. Currently, it has become clear that improving PTP druggability can be an attainable goal, through different medicinal chemistry approaches. Besides the development of allosteric inhibitors of PTPs, the design of PROteolysis-TArgeting Chimeras (PROTACs) has emerged as a promising strategy capable of providing a useful alternative mechanism to control these enzymes through their targeted degradation. Although the development of PROTACs directed to PTPs is still in its infancy, the results so far available are promising; this perspective study focuses on this class of potential novel drugs, highlighting advantages and challenging aspects to consider for future progress. Full article

A new series of 1H-pyrrolo[3,2-g]isoquinolines, diversely substituted at the 3-position either by a heteroaromatic scaffold or by propionate/acrylate side chains, were synthesized and evaluated as Haspin kinase inhibitors. The results of the kinase inhibitory potency study demonstrated that some of the new prepared compounds exhibited low nanomolar potencies toward Haspin. These results indicated that 3-substituted pyrrolo[3,2-g]isoquinolines could serve as intermediates for the development of PROTACs targeting Haspin, with the 3-position allowing further introduction of linkers to tether an E3 ligase ligand. However, this hypothesis remains to be demonstrated. Full article

Gallbladder cancer (GBC), an aggressive malignancy of the biliary tract, is characterized by pronounced geographical variation and a poor prognosis, with a five-year survival rate below 20%. Despite its low global incidence, it ranks as the fifth most prevalent gastrointestinal cancer. The aim of this review is to provide a comprehensive understanding of the molecular mechanisms underpinning GBC progression, with a particular focus on the pivotal role of transcription factors (TFs) in its pathogenesis. This review delineates how aberrant regulation of TFs contributes to tumor initiation, progression, and therapeutic resistance, and to discuss the translational potential of targeting these factors for clinical benefit. Tumor suppressor TFs such as p53 and p16 frequently undergo genetic alterations, including mutations, deletions, or epigenetic silencing, leading to impaired cell cycle control, DNA repair, and apoptosis. Conversely, oncogenic TFs including TCF4, MYBL2, NF-kB, AP-1, Snail, c-MYC, SP1, FOXK1, KLF-5, STAT3 and BIRC7 are often upregulated in GBC, promoting unchecked proliferation, epithelial–mesenchymal transition (EMT), metastasis, and therapeutic resistance. This review aims to bridge current molecular insights with emerging therapeutic approaches, with particular emphasis on innovative interventions such as proteolysis-targeting chimeras (PROTACs), RNA-based therapeutics, CRISPR-driven genome editing, and epigenetic modulators, which collectively represent promising strategies for achieving more effective and personalized treatment outcomes in patients with GBC. Full article