Expert Opinion on Therapeutic Targets最新文献

Introduction: Squalene epoxidase (SQLE) is a pivotal enzyme in sterol biosynthesis, catalyzing the conversion of squalene to 2,3-oxidosqualene. Beyond its core role in cholesterol homeostasis, SQLE is implicated in cancer, hypercholesterolemia, and fungal infections, positioning it as a valuable therapeutic target.

Areas covered: We conducted a comprehensive literature search across primary databases to gather in vitro, in silico, and in vivo evidence on SQLE. This review explores the enzyme's structural and functional features, including substrate specificity and catalytic mechanisms, and examines inhibitor interactions. Computational methods predict enzyme - inhibitor dynamics, guiding drug design, while in vivo investigations clarify SQLE's role in metabolic disorders and tumorigenesis. Challenges include drug resistance and study discrepancies, but emerging technologies, such as cryo-electron microscopy and CRISPR editing, offer new avenues for deeper exploration.

Expert opinion: SQLE is an underexplored yet promising therapeutic target, with particular relevance to oxidative stress, ferroptosis, and gut microbiota research. Overcoming current barriers through advanced technologies and multidisciplinary strategies could propel SQLE-targeted treatments into clinical practice, supporting precision medicine and broader translational applications.

Introduction: The mechanism of action of antidepressants is not fully ascertained. In addition to monoamines, disparate other effectors are also implicated in the molecular and cellular effects of chronic stress including neurogenesis, neurodifferentiation, and neuroplasticity. Evidence suggests sigma-1 receptors (S1Rs) as a putative target and possible mediator of antidepressant activity.

Areas covered: Data from preclinical and clinical trials was synthesized from inception to August 2024. Results showed that S1Rs regulate neurotransmitter availability and release (e.g. monoamines, glutamate), and influence intracellular Ca²⁺ levels as well as immune inflammatory responses. The introduction of the N-Methyl-D-aspartic Acid (NMDA) antagonist/S1R agonist dextromethorphan-bupropion in August of 2022 represented the first time the Food and Drug Administration (FDA) permitted language that the hypothesized mechanism of an antidepressant involved activity at S1Rs. We also describe the physiology, pathophysiology, and function of S1Rs.

Expert opinion: Sigma-1 modulation is relevant to the mechanism of action of agents currently FDA-approved in major depressive disorder (MDD) (e.g. dextromethorphan-bupropion). Modulating sigma-1 systems is fit for purpose as it relates to future therapeutic discoveries and development in depressive and other mental disorders. Whether sigma-1 modulation is uniquely relevant to targeting dimensions of psychopathology that are more difficult to treat (i.e. anhedonia) awaits determination.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that is often diagnosed at a late stage, resulting in poor survival rates and limited treatment options. Several factors contribute to the dismal prognosis of PDAC, including the absence of reliable biomarkers and effective therapies, as well as the complex biology of the disease.

Areas covered: The pathobiology of PDAC encompasses its unique mutational landscape, desmoplastic stroma, and immune suppressive tumor microenvironment (TME). These characteristics are influenced by an intricate network of signaling pathways activated by oncogenic KRAS, DNA damage and repair machinery, metabolic adaptations, and aberrant mucin expression. This review summarizes our current understanding of these pathways to explore their potential for therapeutic vulnerabilities in PDAC. We discuss how recent efforts to elucidate these pathways have identified novel targets and treatments for this dreadful disease.

Expert opinion: The complex biology of PDAC complicates the effectiveness of single therapeutic agents. To achieve durable clinical responses in patients with PDAC, it is essential to simultaneously inhibit multiple parallel or unrelated pathways. Therefore, a combination therapeutic regimen is necessary to significantly improve treatment outcomes that rely solely on biologically driven concepts. These studies suggest ways to expand our understanding of the therapeutic vulnerabilities in PDAC.

Background: Pulmonary arterial hypertension (PAH) is a progressive, life-threatening disease driven by vascular remodeling, right ventricular (RV) dysfunction, and metabolic and inflammatory dysregulation. Current therapies primarily target vasodilation to relieve symptoms but do not reverse disease progression. The recent approval of sotatercept, which modulates BMP/TGF-β signaling, marks a shift toward anti-remodeling therapies. Building on this, recent preclinical advances have identified promising therapeutic targets and potentially disease-modifying treatments.

Areas covered: This review synthesizes the evolving preclinical landscape of emerging PAH therapeutic targets and drugs, highlighting innovative approaches aimed at addressing the underlying mechanisms of disease progression. Additionally, we discuss novel therapeutic strategies under development.

Expert opinion: Recent advances in PAH research have identified novel therapeutic targets beyond vasodilators, including modulation of BMP/TGF-β signaling, metabolic programs, epigenetics, cancer-related signaling, the extracellular matrix, and immune pathways, among others. Sotatercept represents a significant advance in therapies that go beyond vasodilation, and long-term safety, efficacy, and durability are being assessed. Future treatment strategies will focus on precision approaches, noninvasive technologies, and regenerative biology to improve outcomes and reverse vascular remodeling.

Introduction: Despite decreasing trends in incidence, colorectal cancer (CRC) is still a major contributor to malignancy-related morbidities and mortalities. Groundbreaking advances in immunotherapies and targeted therapies benefit a subset of CRC patients, with sub-optimal outcomes. Hence, there is an unmet need to design and manufacture novel therapies, especially for advanced/metastatic disease. KRAS, the most highly mutated proto-oncogene across human malignancies, particularly in pancreatic adenocarcinoma, non-small cell lung cancer, and CRC, is an on-off switch and governs several fundamental cell signaling cascades. KRAS mutations not only propel the progression and metastasis of CRC but also critically modulate responses to targeted therapies.

Areas covered: We discuss the impacts of KRAS mutations on the CRC's tumor microenvironment and describe novel strategies for targeting KRAS and its associated signaling cascades and mechanisms of drug resistance.

Expert opinion: Drug development against KRAS mutations has been challenging, mainly due to structural properties (offering no appropriate binding site for small molecules), critical functions of the wild-type KRAS in non-cancerous cells, and the complex network of its downstream effector pathways (allowing malignant cells to develop resistance). Pre-clinical and early clinical data offer promises for combining KRAS inhibitors with immunotherapies and targeted therapies.

Introduction: Recent seminal neuroscience research has significantly increased our knowledge on cellular and molecular responses of various cells in the pain pathway to peripheral nerve injuries and inflammatory processes. Transcriptomic and epigenetic analysis of primary sensory neurons (PSNs) in animal models of peripheral injuries revealed new insights into altered gene expression profiles and epigenetic modifications, which, via increasing spinal nociceptive input, lead to the development of pain. Among the various classes of molecules involved in driving differential gene expression, protein kinases, the enzymes that catalyze the phosphorylation of molecules, are emerging to control histone modification and chromatin remodeling needed for the alteration in transcriptional activity.

Areas covered: Here, we focused on how protein kinases contribute to transcriptomic changes and pathways of induced reprogramming within PSNs upon peripheral nerve injury and inflammation. We conducted systematic literature search across multiple databases, including PubMed, NIH ClinicalTrials.gov portal and GEOData from 1980 to 2024 and compared protein kinase expression frequencies between publicly available RNA sequencing datasets of PSNs and investigated differences in protein kinase expression levels after peripheral nerve injury.

Expert opinion: Novel findings support a new concept that protein kinases constitute regulatory hubs of reprogramming of PSNs, which offers novel analgesic approaches.

Introduction: EphA2 is a receptor tyrosine kinase that is associated with various pathological conditions. Mutations in EphA2 are linked to cataract, an eye disorder manifesting as lens opacity, and representing one of the most prominent causes of blindness worldwide.

Areas covered: We collected a list of cataract-related EphA2 mutations and positioned them inside the different protein domains to identify regions of the receptor that could be more likely considered targets in the 'anti-cataract' drug discovery field. Moreover, we analyzed the structural consequences these mutations could induce. A search for literature related to EphA2 and cataracts was carried out through the PubMed National Library of Medicine. Structural information on diverse EphA2 domains was obtained from the Protein Data Bank. EphA2 variants connected to cataract were checked on the databases Cat-Map and dbSNP.

Expert opinion: Cataract-related mutations are gathered within diverse EphA2 domains and are abundant inside its Sam (Sterile alpha motif, EphA2-Sam) domain. Mutations affecting EphA2-Sam could disturb domain helical fold and hamper interaction with other Sam domains, eventually interfering with EphA2 cell migration activity. Identification of stabilizing small molecules targeting EphA2-Sam pathogenic variants could represent an original route to discover novel therapeutic compounds against lens opacity.