Current Signal Transduction Therapy - Volume 19, Issue 2, 2024

Regulation of cell proliferation depends on stimulatory and inhibitory factors that act in a coordinated manner in response to external signals. Various agents, including mitogens, growth factors, cytokines, and other external factors, can impact the mitotic cell cycle, resulting in either provoking growth, differentiation, or apoptosis. Many kinases, such as protein kinases, regulate mitotic cell proliferation through normal signalling. One of the major protein kinase family members is cyclin-dependent kinases (CDK), which are responsible for the regulation of cell cycle progression. If the cell cycle-regulatory mechanisms are permanently altered, it can cause abnormal proliferation that leads to neoplasia. This can result in tumour development, where the availability and expression of CDKs become altered, contributing significantly to impaired cell proliferation. Changes like these are often a characteristic of cancer. CDK inhibitors have shown significant clinical benefits in treating various types of tumours in recent years. The output has been achieved by the clinical approvals of particular CDK inhibitors. Researchers have also been studying the proteolysis-targeting chimera (PROTAC) molecule for the last two decades. This molecule uses ubiquitin-mediated proteasome mechanisms to break down specific targets, making it a promising method for targeted protein degradation (TPD). TPD has become a promising therapeutic option for tackling disease-causing proteins that are otherwise challenging to treat using traditional small molecules. This review provides an overview of the state of knowledge and a general understanding of selective or nonselective CDK inhibitors and PROTAC degraders currently under development or clinically approved congeners, focusing on improving cancer therapy.

Atopic dermatitis (AD) is a chronic immune-mediated skin condition seriously affecting both children and adults and impacting their quality of life. This complex condition involves genetic predisposition, immune system impairment, and environmental factors. The Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway plays a key role in AD pathogenesis and progression. Abrocitinib presents a hopeful avenue for managing moderate to severe AD, offering significant symptom relief and potential long-term benefits. Its targeted approach to modulating the JAK-STAT pathway holds promise for improved AD management. This comprehensive review explores AD pathogenesis, the chemistry and clinical pharmacology of Abrocitinib, and its safety and efficacy in various trials.

Background: Aging is a progressive deterioration characterized by the gradual buildup of physiological alterations as time passes. The aging phenomenon encompasses various interconnected systems within the body, such as the skin, bones, cartilage, and hair. Objective and Methods: In this study, based on the appropriate properties of squalene, including antioxidant, anti-inflammatory, and skin repair properties, a molecular docking study was designed for the drug squalene and proteins related to the dermis and epidermis pathway and collagen production (including Col3A1, Col1A2, FBN1, Decorin, and HAS2). Results and Discussion: The docking results indicated that the interaction of squalene with hyaluronan synthetase 2 (HAS2) possessed the highest negative binding free energy value of -10.90 KCal/mol, followed by decorin with a value of -9.99 KCal/mol. Also, the inhibition constant values of squalene- HAS2 and squalene-decorin complexes were equal to 1.61 and 7.51 μM, respectively. It has been stated that decorin (as a small proteoglycan) and HAS2 are involved in controlling the assembly of skin fibrils and the biosynthesis of glucosaminoglycans, respectively. Conclusion: Considering that proteoglycans and glucosaminoglycans play a role in the skin aging process, squalene may be used as an anti-aging agent to induce these pathways and for different purposes. Squalene may be used as a potential agent alone or in combination with other compounds in tissue engineering scaffolds for cosmetic, anti-aging, wound healing, and tissue repair applications.

Hypertension, a condition characterized by elevated blood pressure, poses a significant medical risk, particularly in relation to the development of cardiovascular disease. The pathogenesis of hypertension can be influenced by a combination of genetic and environmental factors. Recent scientific studies have shed light on the involvement of long-non-coding RNAs (lncRNAs) in various diseases, including pulmonary arterial and essential hypertension. These lncRNAs have been found to play crucial roles at the transcriptional, post-transcriptional, and post-translational levels. By targeting endothelial cell proliferation, migration, apoptosis, and angiogenesis, lncRNAs can induce dysfunction in arterial endothelial cells, contributing to the progression of hypertension-related pathological events. Therefore, the abnormal expression of lncRNAs has emerged as a significant factor in the understanding of essential hypertension and its associated mechanisms. To further our understanding, we conducted a comprehensive review focusing on unraveling the functional roles of lncRNAs in essential hypertension.

One of the most prevalent cancers throughout the world is colorectal cancer (CRC). Natriuretic peptides are important hormones that have a crucial role in the physiology of humans and other animals. There are a variety of treatments for colon cancer. However, conventional therapies have many side effects and low efficacy in the treatment of this disease. Atrial Natriuretic Peptide (ANP) is one of the most well-known natriuretic peptides involved in regulating blood pressure and blood volume. Studies have demonstrated that ANP has a therapeutic effect on different cancer types. The anti-tumor effect of ANP is exerted by inhibiting DNA synthesis but not inducing apoptosis. The anti-proliferative role of ANP has been reported in human breast, prostate, colon, pancreatic, lung, and ovarian cancer and in many other tumors. Therefore, we review the recent papers on natriuretic peptides in CRC as a common malignancy in adults to assess the pathways of ANP involved in the progression of CRC and its effects on the prevention or treatment of CRC and other cancer types.

Background: Deficiency of insulin signaling in type 2 diabetes results from insulin resistance or defective insulin secretion and induced hyperglycemia. By reducing glycated hemoglobin, SGLT2 inhibitors improve hyperuricemia, blood lipids, and weight loss without increasing the risk of hypoglycemia. By targeting this pathway, SGLT2 inhibitors can become a prominent target in the management of type 2 diabetes. Objective: This study aimed to carry out the molecular docking and ADMET prediction of novel imidazo(2,1-b)-1,3,4 thiadiazole derivatives as SGLT2 inhibitors. Methods: The chemical structures of 108 molecules were drawn by using ChemDraw Professional 15.0. Further, their energy minimization was also carried out by using Chem Bio Draw three-dimensional (3D) Ultra 12.0. Molecular docking was also carried out using a Molegro Virtual Docker to identify the best-fitting molecules and to identify the potential leads on the basis of dock score. The predicted parameters of drug-likeness according to Lipinski’s rule of five, such as molecular weight, log P, hydrogen bond acceptor, hydrogen bond donors, and number of rotatable bonds of the selected compounds, were predicted using pKCSM software. Results: About 108 molecules were designed by employing different substitutions on imidazothiadiazole nucleus as SGLT2 inhibitors. Out of these, 10 compounds were found to have better interactions with the active site of SGLT2 protein and the highest dock scores compared to canagliflozin. Compounds 39a and 39b demonstrated good interactions and the highest docking scores of -155.428 and -142.786, respectively. The in silico physicochemical properties of the best compounds were also determined. Additionally, these compounds suggested a good pharmacokinetic profile as per Lipinski's rule of five (orally active drugs). Conclusion: Novel imidazo (2,1-b)-1,3,4 thiadiazole derivatives were strategically designed, and their binding affinity was meticulously evaluated against the SGLT2 protein. This endeavor yielded pioneering lead compounds characterized by ultimate binding affinity, coupled with optimal ADMET properties in adherence to Lipinski' rule of five and favourable noncarcinogenic profile.