Search

One of the major obstacles to sustained cancer treatment effectiveness is the development of medication resistance. Current therapies that block proteins associated with cancer progression often lose their efficacy due to acquired drug resistance, which is frequently driven by mutated or overexpressed protein targets. Proteolysis-targeting chimeras (PROTACs) offer an alternative therapeutic strategy by hijacking the cell's ubiquitin-proteasome system to degrade disease-causing proteins, presenting several potential advantages. Over the past few years, PROTACs have been developed to target various cancer-related proteins, offering new treatment options for patients with previously untreatable malignancies and serving as a foundation for next-generation therapeutics. One of the notable benefits of PROTACs is their ability to overcome certain resistance mechanisms that limit the effectiveness of conventional targeted therapies, as shown in several recent studies. Additionally, research teams are investigating how PROTACs can selectively degrade mutant proteins responsible for resistance to first-line cancer therapies. In the pursuit of novel and effective treatments, this review highlights recent advancements in the development of PROTACs aimed at overcoming cancer resistance. When it comes to drug design, heterocyclic scaffolds often serve as a foundational framework, offering opportunities for modification and optimization of novel molecules. Researchers are similarly exploring various heterocyclic derivatives as "warheads" in the design of PROTACs has been instrumental in pushing the boundaries of targeted protein degradation. As warheads, these heterocyclic compounds are responsible for recognizing and binding to the target protein, which ultimately leads to its degradation via the ubiquitin-proteasome system. This study aims to provide a comprehensive overview of cutting-edge strategies in PROTAC design, offering detailed insights into key concepts and methodologies for creating effective PROTACs. Special emphasis is placed on structure-based rational design, the development of novel warheads, and their critical in influencing biological activity., Competing Interests: Declaration of competing interest On behalf of all co-authors, I declare that we do not have any competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Almost 80% of lung cancer diagnoses each year correspond to non-small cell lung cancer (NSCLC). The percentage of NSCLC with EGFR overexpression ranges from 40% to 89%, with squamous tumors showing the greatest rates (89%) and adenocarcinomas showing the lowest rates (41%). Therefore, in NSCLC therapy, blocking the EGFR-driven pathway by inhibiting the intracellular tyrosine kinase domain of EGFR has exhibited significant improvement. In this view, several small molecules particularly pyrimidine/fused pyrimidine scaffolds were intended for molecular hybridization to develop EGFR-TK inhibitors. However, the associated limitation such as resistance and genetic mutation along with adverse effects, constrained the long-term treatment and effectiveness of such medication. Therefore, in recent years, pyrimidine derivatives were uncovered as potential EGFR TKIs. The present review summarised the research progress of EGFR TKIs to dazed structure-activity relationship, biological evaluation, and comparative docking studies of pyrimidine compounds. We have added the comparative docking analysis followed by the molecular simulation study against the four different PDBs of EGFR to strengthen the already existing research. Docking analysis unfolded that compound 14 resulted as noticeable with all different PDB and managed to interact with some of the crucial amino acid residues. From a future perspective, researchers must develop a more selective inhibitor, that can selectively target the mutation. Our review will support medicinal chemists in the direction of the development of novel pyrimidine-based EGFR TKIs.Communicated by Ramaswamy H. Sarma.

Cancer is a major societal, public health, and economic burden in the 21st century, with 9.7 million deaths in 2022 (9.96 million in 2020) and 20 million new cancer cases (19.6 million in 2020). Considering the increasing number of cancer cases and deaths, heterocyclic compounds always paved the gold mine for the development of potential anticancer drugs as these compounds have unique flexibility and dynamic cores. Benzothiazoles and their derivatives have potential anticancer properties, making them a desirable scaffold among different heterocycles. Title structures are a class of chemicals that may bind to various receptors with high affinity, particularly those engaged in oncogenic processes. The use of these compounds allows medicinal chemists to rapidly produce anticancer treatments across a large range of targets over an extended length of time. The current study presents a thorough success story of benzothiazole derivatives as anticancer agents. It discusses the current state of cancer, the profile of benzothiazole-based derivatives synthetic pathways, and its relevance as an anticancer agent on several oncogenic pathways. The structure-activity relationship was also added to offer insight into the connection of biological data with structure and the rational design of more active drugs., Competing Interests: Declaration of competing interest On the behalf of all co-author, I declared that we do not have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

Epidermal growth factor receptor (EGFR) and its subtype human epidermal growth factor receptor 2 (HER2) gets activated when its endogenous ligand(s) bind to its ATP binding site of target receptors. In breast cancer (BC), EGFR and HER2 are two proteins are overexpressed which leads to overexpression of cells proliferation and decreases cell death/apoptosis. Pyrimidine is one of the most widely studied heterocyclic scaffolds for EGFR as well as HER2 inhibition. We gather some remarkable results for fused-pyrimidine derivatives on various cancerous cell lines ( in-vitro ) and animal ( in-vivo ) evaluation to highlight their potency. The heterocyclic (five, six-membered, etc.) moieties which are coupled with pyrimidine moiety are potent against EGFR and HER2 inhibitions. Hence structure-activity relationship (SAR) plays important role in study of heterocyclic moiety along pyrimidine and effects of substituents, groups for increase or decrease in the cancerous activity and toxicity. By thoughtful of fused pyrimidines SAR study, it facilitates in receiving excellent overview of the compounds by concerning of efficacy and potential summary for future EGFR inhibitors. Furthermore, we studied the in-silico interactions of synthesized compounds to evaluate binding affinity towards the key amino acids..Communicated by Ramaswamy H. Sarma.

The pyrimidine and fused pyrimidine ring systems play vital roles to inhibit the c-Src kinase. The Src kinase is made of different domains but the kinase domain is responsible for inhibition of Src kinase. In which the kinase domain is the main domain that is made of several amino acids. The Src kinase is inhibited by its inhibitors when it is activated by phosphorylation. Although dysregulation of Src kinase caused cancer in the late nineteenth century, medicinal chemists have not explored it extensively; therefore it is still regarded as a cult pathway. There are numerous FDA-approved drugs on the market, yet novel anticancer drugs are still in demand. Existing medications have adverse effects and drug resistance owing to rapid protein mutation. In this review, we discussed the activation process of Src kinase, chemistry of pyrimidine ring and its different synthetic routes, as well as the recent development in c-Src kinase inhibitors containing pyrimidine and their biological activity, SAR, and selectivity. The c-Src binding pocket has been predicted in detail to discover the vital amino acids which will interact with inhibitors. The potent derivatives were docked to discover the binding pattern. The derivative 2 established three hydrogen bonds with the amino acid residues Thr341 and Gln278 and had the greatest binding energy of -13.0 kcal/mol. The top docked molecules were further studied for ADMET studies. The derivative 1 , 2, and 43 did not show any violation of Lipinski's rule. All derivatives used for the prediction of toxicity showed toxicity.

JAK-STAT signalling pathway was discovered more than quarter century ago. The JAK-STAT pathway protein is considered as one of the crucial hubs for cytokine secretion which mediates activation of different inflammatory, cellular responses and hence involved in different etiological factors. The various etiological factors involved are haematopoiesis, immune fitness, tissue repair, inflammation, apoptosis, and adipogenesis. The presence of the active mutation V617K plays a significant role in the progression of the JAK-STAT pathway-related disease. Consequently, targeting the JAK-STAT pathway could be a promising therapeutic approach for addressing a range of causative factors. In this current review, we provided a comprehensive discussion for the in-detail study of anatomy and physiology of the JAK-STAT pathway which contributes structural domain rearrangement, activation, and negative regulation associated with the downstream signaling pathway, relationship between different cytokines and diseases. This review also discussed the recent development of clinical trial entities. Additionally, this review also provides updates on FDA-approved drugs. In the current investigation, we have classified recently developed small molecule inhibitors of JAK-STAT pathway according to different chemical classes and we emphasized their synthetic routes, biological evaluation, selectivity, and structure-activity relationship., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Breast cancer (BC) is a second common malignancy in female globally. Hence, identification of novel therapeutic agents is extremely important. Molecular docking and MD simulation are the important tools in the process of drug discovery for searching the potential hits. The structure-based drug designing technique also reveals the information about ligands behavior in computational environment. Docking tools help in visualization and analysis of protein-ligand complex at atomic level. Molecular dynamics shows the stability of the molecules in the receptor cavity in the simulated environment. In this research work, we have screened potent phytochemicals against the BC. We docked the phytochemicals and examined the binding affinities of ligands towards the EGFR, HER2, estrogen and NF- κ B receptors. Pristimerin, ixocarpalactone A, viscosalactone B and zhankuic acid A have shown higher binding affinities and energies towards targeted receptors among the screened phytochemicals. MD simulation study shows stability of docked complex for pristimerin and HER2 receptor. These phytochemicals can be repurposed for their anticancer activity. This in-silico work provides a strong ground for further investigation of their anticancer activity.