NLRP3 inflammasome in atherosclerosis: Mechanisms and targeted therapies.

Atherosclerosis (AS) is the primary pathology behind various cardiovascular diseases and the leading cause of death and disability globally. Recent evidence suggests that AS is a chronic vascular inflammatory disease caused by multiple factors. In this context, the NLRP3 inflammasome, acting as a signal transducer of the immune system, plays a critical role in the onset and progression of AS. The NLRP3 inflammasome is involved in endothelial injury, foam cell formation, and pyroptosis in AS. Therefore, targeting the NLRP3 inflammasome offers a new treatment strategy for AS. This review highlights the latest insights into AS pathogenesis and the pharmacological therapies targeting the NLRP3 inflammasome, focusing on optimal targets for small molecule inhibitors. These insights are valuable for rational drug design and the pharmacological assessment of new targeted NLRP3 inflammasome inhibitors in treating AS.

Targeting the Molecules in EMT: A Potential Therapeutic Opportunity in Breast Cancer.

Breast Cancer (BC) is one of the most frequently occurring diseases in women, accounting for 90% of cancer-related deaths in women. Tumor cells can invade nearby tissues and spread to distant organs by metastasis. The epithelialmesenchymal transition or EMT, which involves a number of transcription factors and signaling pathways, is a mechanism by which cells of the epithelium change into mesenchymal type capable of motility, invasion, and metastasis. EMT has grown to be a more intriguing target for developing cutting-edge treatment approaches since it is involved in diverse malignant transformation-related activities. Besides preventing tumor cell invasion and spread and the development of metastatic lesions, anti-EMT treatment methods also lessen cancer stemness and improve the efficacy of more traditional chemotherapeutics. EMT is, therefore, a desirable target in oncology. This review gives an overview of EMT, various markers of EMT, and different inhibitors used in therapies targeting EMT in BC.

Development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry method to quantify the small molecule inhibitors adagrasib, alectinib, brigatinib, capmatinib, crizotinib, lorlatinib, selpercatinib, and sotorasib in human plasma.

Small molecule inhibitors (SMIs) are increasingly being used in the treatment of non-small cell lung cancer. To support pharmacokinetic research and clinical treatment monitoring, our aim was to develop and validate an ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) assay for quantification of eight SMIs: adagrasib, alectinib, brigatinib, capmatinib, crizotinib, lorlatinib, selpercatinib, and sotorasib. Development of the UPLC-MS/MS assay was done by trying different columns and eluents to optimize peak shape. The assay was validated based on guidelines of the European Medicines Agency. Chromatographic separation was performed with a gradient elution using ammonium formate in water and methanol. Detection was performed using a triple quadrupole tandem mass spectrometer with electrospray ionization. Validation was performed in a range of 10-2500 µg/L for lorlatinib, 25-6250 µg/L for alectinib and crizotinib, 25-10,000 µg/L for capmatinib and selpercatinib, 50-12,500 µg/L for brigatinib, and 100-25,000 µg/L for adagrasib and sotorasib. Imprecision was <8.88% and inaccuracy was <12.5% for all compounds. Seven out of eight compounds were stable for 96 h at room temperature. Sotorasib was stable for 8 h at room temperature. A sensitive and reliable method has been developed to quantify eight SMIs with a single assay, enhancing efficacy and safety of targeted therapies.

Unlocking the potential: advancements and future horizons in ROR1-targeted cancer therapies.

While receptor tyrosine kinase-like orphan receptor 1 (ROR1) is typically expressed at low levels or absent in normal tissues, its expression is notably elevated in various malignant tumors and conditions, including chronic lymphocytic leukemia (CLL), breast cancer, ovarian cancer, melanoma, and lung adenocarcinoma. This distinctive feature positions ROR1 as an attractive target for tumor-specific treatments. Currently, several targeted drugs directed at ROR1 are undergoing clinical development, including monoclonal antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor T-cell therapy (CAR-T). Additionally, there are four small molecule inhibitors designed to bind to ROR1, presenting promising avenues for the development of PROTAC degraders targeting ROR1. This review offers updated insights into ROR1's structural and functional characteristics, embryonic development implications, cell survival signaling pathways, and evolutionary targeting strategies, all of which have the potential to advance the treatment of malignant tumors.

Extracellular heat shock protein 90 alpha (eHsp90α)'s role in cancer progression and the development of therapeutic strategies.

Heat shock protein 90 alpha (Hsp90α) is an abundantly expressed and evolutionarily conserved molecular chaperone. Hsp90α is the inducible Hsp90 isoform, and its expression and secretion extracellularly (eHsp90α) can be triggered in response to a variety of cellular stresses to protect/activate client proteins and to facilitate cellular adjustment to the stress. As a result, cancers often have high expression levels of intracellular and extracellular (plasma) Hsp90α, allowing them to support their oncogenesis and progression. In fact, (e)Hsp90α has been implicated in regulating processes such as cell signaling transduction, DNA repair, promotion of the Epithelial-to-Mesenchymal Transition (EMT), promotion of angiogenesis, immune response, and cell migration. Hsp90α levels have been correlated with cancer progression and severity in several cancers, indicating that it may be a useful biomarker or drug-target for cancer. To date, the development of intracellular Hsp90α-targeted therapies include standard N-terminal ATP-competitive inhibitors and allosteric regulators that bind to Hsp90α's middle or C-terminal domain. On-target toxicities and dosing complications as a result of Hsp90α inhibition has driven the development of eHsp90α-targeted therapies. Examples include anti-Hsp90α monoclonal antibodies and cell-impermeable Hsp90α small molecule inhibitors. This review aims to discuss the many roles Hsp90α plays in cancer progression with a focus on the current development of Hsp90α-targeted therapies.

Small Molecules in the Management of Psoriasis and Psoriatic Arthritis.

Psoriasis is a common chronic, immune-mediated inflammatory skin disease associated with various comorbidities. Managing psoriasis is often challenging as the therapy is decided based on the area of the disease, associated comorbidities and impairment in quality of life, besides the patient's preference. Making progress in the development of new molecules that can be used topically or orally, effectively controlling the disease with minimal side effects and providing long-lasting remissions are the needs of the hour. Recent developments in understanding the complexities of the pathogenesis of psoriasis have resulted in the reinforcement of treatment modalities, leading to the evolution of various biologics and small-molecule inhibitors. In comparison with biologics, both patients and treating physicians prefer small molecules for various reasons such as avoiding injections and side effects that are associated with biologics biologics. Moreover small molecules are economical than biologics. Newer small molecules, both topical and oral, are promising additions to the therapeutic arsenal in the management of psoriasis in the future.

Recent Advances in representative small-molecule DRD2 inhibitors: Synthetic Routes and clinical applications.

The dopamine D2 receptor (DRD2) represents a pivotal target for therapeutic intervention in the treatment of neuropsychiatric disorders, including schizophrenia, bipolar disorder, and Parkinson's disease. The successful discovery of numerous effective DRD2 inhibitors has led to their clinical application and ongoing evaluation in various clinical trials. This review explores the synthetic approaches and clinical applications of prototypical small-molecule DRD2 inhibitors that have received approval or are currently undergoing clinical trials, highlighting their therapeutic potential and challenges. The synthesis of these inhibitors employs various chemical strategies, including modifications of phenothiazine and butyrophenone structures, which have yielded significant antipsychotic agents like chlorpromazine and haloperidol. Additionally, newer classes of inhibitors, such as aripiprazole, exhibit partial agonist activity at DRD2, offering a unique therapeutic profile. Clinically, DRD2 inhibitors demonstrate efficacy in managing positive symptoms of schizophrenia, manic episodes in bipolar disorder, and dopaminergic imbalance in Parkinson's disease. However, the emergence of adverse effects, including tardive dyskinesia, extrapyramidal symptoms and metabolic syndrome, presents substantial challenges. Advances in the development of second-generation antipsychotics aim to balance efficacy with a better side effect profile by targeting additional neurotransmitter receptors. This review aims to deliver an overview of the synthesis and clinical applications of representative small-molecule DRD2 inhibitors across various clinical phases, thereby offering strategic insights for the advancement of DRD2 inhibitor development.

Versatile function of NF-ĸB in inflammation and cancer.

Nuclear factor-kappaB (NF-ĸB) plays a crucial role in both innate and adaptive immune systems, significantly influencing various physiological processes such as cell proliferation, migration, differentiation, survival, and stemness. The function of NF-ĸB in cancer progression and response to chemotherapy has gained increasing attention. This review highlights the role of NF-ĸB in inflammation control, biological mechanisms, and therapeutic implications in cancer treatment. NF-ĸB is instrumental in altering the release of inflammatory factors such as TNF-α, IL-6, and IL-1ß, which are key in the regulation of carcinogenesis. Specifically, in conditions including colitis, NF-ĸB upregulation can intensify inflammation, potentially leading to the development of colorectal cancer. Its pivotal role extends to regulating the tumor microenvironment, impacting components such as macrophages, fibroblasts, T cells, and natural killer cells. This regulation influences tumorigenesis and can dampen anti-tumor immune responses. Additionally, NF-ĸB modulates cell death mechanisms, notably by inhibiting apoptosis and ferroptosis. It also has a dual role in stimulating or suppressing autophagy in various cancers. Beyond these functions, NF-ĸB plays a role in controlling cancer stem cells, fostering angiogenesis, increasing metastatic potential through EMT induction, and reducing tumor cell sensitivity to chemotherapy and radiotherapy. Given its oncogenic capabilities, research has focused on natural products and small molecule compounds that can suppress NF-ĸB, offering promising avenues for cancer therapy.

Why Is Wnt/ß-Catenin Not Yet Targeted in Routine Cancer Care?

Despite significant progress in cancer prevention, screening, and treatment, the still limited number of therapeutic options is an obstacle towards increasing the cancer cure rate. In recent years, many efforts were put forth to develop therapeutics that selectively target different components of the oncogenic Wnt/ß-catenin signaling pathway. These include small molecule inhibitors, antibodies, and more recently, gene-based approaches. Although some of them showed promising outcomes in clinical trials, the Wnt/ß-catenin pathway is still not targeted in routine clinical practice for cancer management. As for most anticancer treatments, a critical limitation to the use of Wnt/ß-catenin inhibitors is their therapeutic index, i.e., the difficulty of combining effective anticancer activity with acceptable toxicity. Protecting healthy tissues from the effects of Wnt/ß-catenin inhibitors is a major issue due to the vital role of the Wnt/ß-catenin signaling pathway in adult tissue homeostasis and regeneration. In this review, we provide an up-to-date summary of clinical trials on Wnt/ß-catenin pathway inhibitors, examine their anti-tumor activity and associated adverse events, and explore strategies under development to improve the benefit/risk profile of this therapeutic approach.

Development and therapeutic potential of DNA-dependent protein kinase inhibitors.

The deployment of DNA damage response (DDR) combats various forms of DNA damage, ensuring genomic stability. Cancer cells' propensity for genomic instability offers therapeutic opportunities to selectively kill cancer cells by suppressing the DDR pathway. DNA-dependent protein kinase (DNA-PK), a nuclear serine/threonine kinase, is crucial for the non-homologous end joining (NHEJ) pathway in the repair of DNA double-strand breaks (DSBs). Therefore, targeting DNA-PK is a promising cancer treatment strategy. This review elaborates on the structures of DNA-PK and its related large protein, as well as the development process of DNA-PK inhibitors, and recent advancements in their clinical application. We emphasize our analysis of the development process and structure-activity relationships (SARs) of DNA-PK inhibitors based on different scaffolds. We hope this review will provide practical information for researchers seeking to develop novel DNA-PK inhibitors in the future.

GRP78 inhibitor YUM70 upregulates 4E-BP1 and suppresses c-MYC expression and viability of oncogenic c-MYC tumors.

The 78-kDa glucose regulated protein (GRP78) commonly upregulated in a wide variety of tumors is an important prognostic marker and a promising target for suppressing tumorigenesis and treatment resistance. While GRP78 is well established as a major endoplasmic reticulum (ER) chaperone with anti-apoptotic properties and a master regulator of the unfolded protein response, its new role as a regulator of oncoprotein expression is just emerging. MYC is dysregulated in about 70 % of human cancers and is the most commonly activated oncoprotein. However, despite recent advances, therapeutic targeting of MYC remains challenging. Here we identify GRP78 as a new target for suppression of MYC expression. Using multiple MYC-dependent cancer models including head and neck squamous cell carcinoma and their cisplatin-resistant clones, breast and pancreatic adenocarcinoma, our studies revealed that GRP78 knockdown by siRNA or inhibition of its activity by small molecule inhibitors (YUM70 or HA15) reduced c-MYC expression, leading to onset of apoptosis and loss of cell viability. This was observed in 2D cell culture, 3D spheroid and in xenograft models. Mechanistically, we determined that the suppression of c-MYC is at the post-transcriptional level and that YUM70 and HA15 treatment potently upregulated the eukaryotic translation inhibitor 4E-BP1, which targets eIF4E critical for c-MYC translation initiation. Furthermore, knock-down of 4E-BP1 via siRNA rescued YUM70-mediated c-MYC suppression. As YUM70 is also capable of suppressing N-MYC expression, this study offers a new approach to suppress MYC protein expression through knockdown or inhibition of GRP78.

MYB as a Critical Transcription Factor and Potential Therapeutic Target in AML.

Myb was identified over four decades ago as the transforming component of acute leukemia viruses in chickens. Since then it has become increasingly apparent that dysregulated MYB activity characterizes many blood cancers, including acute myeloid leukemia, and that it represents the most "addictive" oncoprotein in many, if not all, such diseases. As a consequence of this tumor-specific dependency for MYB, it has become a major focus of efforts to develop specific antileukemia drugs. Much attention is being given to ways to interrupt the interaction between MYB and cooperating factors, in particular EP300/KAT3B and CBP/KAT3A. Aside from candidates identified through screening of small molecules, the most exciting prospect for novel drugs seems to be the design of peptide mimetics that interfere directly at the interface between MYB and its cofactors. Such peptides combine a high degree of target specificity with good efficacy including minimal effects on normal hematopoietic cells.

TRIP13 - a potential drug target in cancer pharmacotherapy.

ATPases Associated with Diverse Cellular Activity (AAA+ATPases) are important enzymatic functional proteins in human cells. Thyroid Hormone Receptor Interacting Protein-13 (TRIP13) is a member of this protein superfamily, that partly regulates DNA repair pathways and spindle assembly checkpoints during mitosis. TRIP13 is reported as an oncogene involving multiple pathways in many human malignancies, including multiple myeloma, brain tumors, etc. The structure of TRIP13 reveals the mechanisms for ATP binding and how TRIP13 recognizes the Mitotic Arrest Deficiency-2 (MAD2) protein, with p31comet acting as an adapter protein. DCZ0415, TI17, DCZ5417, and DCZ5418 are the reported small-molecule inhibitors of TRIP13, which have been demonstrated to inhibit TRIP13's biological functions significantly and effective in suppressing various types of malignant cells, indicating that TRIP13 is a significant anticancer drug target. Currently, no systematic reviews are cutting across the functions, structure, and novel inhibitors of TRIP13. This review provides a comprehensive overview of TRIP13's biological functions, its roles in eighteen different cancers, four small molecule inhibitors, different underlying molecular mechanisms, and its functionality as a potential anticancer drug target.

Emerging role of glutathione peroxidase 4 in myeloid cell lineage development and acute myeloid leukemia.

Phospholipid Hydroperoxide Gluthatione Peroxidase also called Glutathione Peroxidase 4 is one of the 25 described human selenoproteins. It plays an essential role in eliminating toxic lipid hydroxy peroxides, thus inhibiting ferroptosis and favoring cell survival. GPX4 is differentially expressed according to myeloid differentiation stage, exhibiting lower expression in hematopoietic stem cells and polymorphonuclear leucocytes, while harboring higher level of expression in common myeloid progenitors and monocytes. In addition, GPX4 is highly expressed in most of acute myeloid leukemia (AML) subtypes compared to normal hematopoietic stem cells. High GPX4 expression is consistently correlated to poor prognosis in patients suffering AML. However, the role of GPX4 in the development of the myeloid lineage and in the initiation and progression of myeloid leukemia remains poorly explored. Given its essential role in the detoxification of lipid hydroperoxides, and its overexpression in most of myeloid malignancies, GPX4 inhibition has emerged as a promising therapeutic strategy to specifically trigger ferroptosis and eradicate myeloid leukemia cells. In this review, we describe the most recent advances concerning the role of GPX4 and, more generally ferroptosis in the myeloid lineage and in the emergence of AML. We also discuss the therapeutic interest and limitations of GPX4 inhibition alone or in combination with other drugs as innovative therapies to treat AML patients.

Estrogen-related receptor, a molecular target against lepidoptera pests.

Until recently, chemical pesticides were one of the most effective means of controlling agricultural pests; therefore, the search for insecticide targets for agricultural pests has been an ongoing problem. Estrogen-related receptors (ERRs) are transcription factors that regulate cellular metabolism and energy homeostasis in animals. Silkworms are highly sensitive to chemical pesticides, making them ideal models for pesticide screening and evaluation. In this study, we detected ERR expression in key organs involved in pesticide metabolism in silkworms (Bombyx mori), including the fat body and midgut. Using ChIP-seq technology, many estrogen- related response elements were identified in the 2000-bp promoter region upstream of metabolism-related genes, almost all of which were potential ERR target genes. The ERR inhibitor, XCT-790, and the endocrine disruptor, bisphenol A, significantly inhibited expression of the ERR target genes, BmTreh-1, BmTret-1, BmPK, BmPFK, and BmHK, in the fat bodies of silkworms, resulting in pupation difficulties in silkworm larvae that ultimately lead to death. In addition, based on the clarification that the ERR can bind to XCT-790, as observed through biofilm interferometry, its three-dimensional spatial structure was predicted, and using molecular docking techniques, small-molecule compounds with a stronger affinity for the ERR were identified. In summary, utilizing the powerful metabolic regulatory function of ERR in Lepidoptera pests, the developed small molecule inhibitors of ERR can be used for future control of Lepidoptera pests.

Small molecule inhibitors targeting heat shock protein 90: An updated review.

As a molecular chaperone, heat shock protein 90 (HSP90) plays important roles in the folding, stabilization, activation, and degradation of over 500 client proteins, and is extensively involved in cell signaling, proliferation, and survival. Thus, it has emerged as an important target in a variety of diseases, including cancer, neurodegenerative diseases, and viral infections. Therefore, targeted inhibition of HSP90 provides a valuable and promising therapeutic strategy for the treatment of HSP90-related diseases. This review aims to systematically summarize the progress of research on HSP90 inhibitors in the last five years, focusing on their structural features, design strategies, and biological activities. It will refer to the natural products and their derivatives (including novobiocin derivatives, deguelin derivatives, quinone derivatives, and terpenoid derivatives), and to synthetic small molecules (including resorcinol derivatives, pyrazoles derivatives, triazole derivatives, pyrimidine derivatives, benzamide derivatives, benzothiazole derivatives, and benzofuran derivatives). In addition, the major HSP90 small-molecule inhibitors that have moved into clinical trials to date are also presented here.

Computational Screening of Repurposed Drugs for HMG-CoA Synthase 2 in Alzheimer's Disease.

Background: HMGCS2 (mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2) plays a pivotal role as a control enzyme in ketogenesis, and its association with the amyloid-ß protein precursor (AßPP) in mitochondria implicates a potential involvement in Alzheimer's disease (AD) pathophysiology. Objective: Our study aimed at identifying repurposed drugs using the DrugBank database capable of inhibiting HMGCS2 activity. Methods: Exploiting the power of drug repurposing in conjunction with virtual screening and molecular dynamic (MD) simulations against 'HMGCS2', we present new in-silico insight into structure-based drug repurposing. Results: The initial molecules were screened for their binding affinity to HMGCS2. Subsequent interaction analyses and extensive 300 ns MD simulations were conducted to explore the conformational dynamics and stability of HMGCS2 in complex with the screened molecules, particularly Penfluridol and Lurasidone. Conclusions: The study revealed that HMGCS2 forms stable protein-ligand complexes with Penfluridol and Lurasidone. Our findings indicate that Penfluridol and Lurasidone competitively bind to HMGCS2 and warrant their further exploration as potential repurposed molecules for anti-Alzheimer's drug development.

Elucidating the Role of Lipid-Metabolism-Related Signal Transduction and Inhibitors in Skin Cancer.

Lipids, as multifunctional molecules, play a crucial role in a variety of cellular processes. These include regulating membrane glycoprotein functions, controlling membrane trafficking, influencing apoptotic pathways, and affecting drug transport. In addition, lipid metabolites can alter the surrounding microenvironment in ways that might encourage tumor progression. The reprogramming of lipid metabolism is pivotal in promoting tumorigenesis and cancer progression, with tumors often displaying significant changes in lipid profiles. This review concentrates on the essential factors that drive lipid metabolic reprogramming, which contributes to the advancement and drug resistance in melanoma. Moreover, we discuss recent advances and current therapeutic strategies that employ small-molecule inhibitors to target lipid metabolism in skin cancers, particularly those associated with inflammation and melanoma.

One problem, multiple potential targets: Where are we now in the development of small molecule inhibitors against Shiga toxin?

Shiga toxin-producing Escherichia coli (STEC) are a group of enteric pathogens which carry phage-encoded Shiga toxins (Stx). STEC infections begin with severe abdominal pain and non-bloody diarrhoea, which can progress to bloody diarrhoea after approximately 4-days post-infection. In high-risk groups such as children and the elderly, patients may develop haemolytic uremic syndrome (HUS). HUS is characterised by microangiopathic haemolytic anaemia, thrombocytopenia, and in severe disease acute renal failure. Traditional antibiotics have been linked with increased toxin production due to the activation of recA-mediated bacterial stress response, resulting in poorer patient outcomes. Therefore, treatment relies on supportive therapies. Antivirulence strategies have been explored as an alternative treatment for bacterial infections and blockers of virulence factors such as the Type III Secretion System. Recent improvements in the mechanistic understanding of the Stx pathway have led to the design of inhibitors to disrupt the pathway, leading to toxin-mediated ribosome damage. However, compounds have yet to progress beyond Phase III clinical trials successfully. This review explores the progress in developing small molecule inhibitors by collating lead compounds derived from in-silico and experimental approaches.

Structural Insights of PD-1/PD-L1 Axis: An In silico Approach.

BACKGROUND: Interaction of PD-1 protein (present on immune T-cell) with its ligand PD-L1 (over-expressed on cancerous cell) makes the cancerous cell survive and thrive. The association of PD-1/PD-L1 represents a classical protein-protein interaction (PPI), where receptor and ligand binding through a large flat surface. Blocking the PD-1/PDL-1 complex formation can restore the normal immune mechanism, thereby destroying cancerous cells. However, the PD-1/PDL1 interactions are only partially characterized. OBJECTIVE: We aim to comprehend the time-dependent behavior of PD-1 upon its binding with PD-L1. METHOD: The current work focuses on a molecular dynamics simulation (MDs) simulation study of apo and ligand bound PD-1. RESULTS: Our simulation reveals the flexible nature of the PD-1, both in apo and bound form. Moreover, the current study also differentiates the type of strong and weak interactions which could be targeted to overcome the complex formation. CONCLUSION: The current article could provide a valuable structural insight about the target protein (PD-1) and its ligand (PD-L1) which could open new opportunities in developing small molecule inhibitors (SMIs) targeting either PD-1 or PD-L1.