Medicinal chemistry perspective of JAK inhibitors: synthesis, biological profile, selectivity, and structure activity relationship.

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.

An updated literature on BRAF inhibitors (2018-2023).

BRAF is the most common serine-threonine protein kinase and regulates signal transduction from RAS to MEK inside the cell. The BRAF is a highly active isoform of RAF kinase. BRAF has two domains such as regulatory and kinase domains. The BRAF inhibitors bind in the c-terminus of the kinase domain and inhibit the downstream pathways. The mutation occurs mainly in the A-loop of the kinase domain. The mutation occurs due to a conversion of valine to glutamate/lysine/arginine/aspartic acid at 600th position. Among the diverse mutations, BRAFV600E is the most common and responsible for numerous cancer such as melanoma, colorectal, ovarian, and thyroid cancer. Due to mutations in RAC1, loss of PTEN, NF1, CCND1, USP28-FBW7 complex, COT overexpression, and CCND1 amplification, the BRAF kinase enzyme developed resistance over the commercially available BRAF inhibitors. There is still unmute urgence for the development of BRAF inhibitors to overcome the persistent limitation such as resistance, mutation, and adverse effects of drugs. In the current study, we described the structure, activation, downstream signaling pathway, and mutation of BRAF. Our group also provided a detailed review of BRAF inhibitors from the last five years (2018-2023) highlighting the structure-activity relationship, mechanistic study, and molecular docking studies. We hope that the current analysis will be a useful resource for researchers and provide chemists a glimpse into the future as design and development of more effective and secure BRAF kinase inhibitors. The development of BRAF inhibitors to overcome the persistent limitation such as resistance, mutation, and adverse effects of drugs. In depth description about different heterocyclic scaffolds (quinoline, imidazole, pyridine, triazole, pyrrole etc.) as BRAF inhibitors from the last five years (2018-2023) highlighting the structure-activity relationship, mechanistic study, and molecular docking studies.

Medicinal Chemistry Perspectives on Recent Advances in Src Kinase Inhibitors as a Potential Target for the Development of Anticancer Agents: Biological Profile, Selectivity, Structure-Activity Relationship.

The physiological Src proto-oncogene is a protein tyrosine kinase receptor that served as the essential signaling pathway in different types of cancer. Src kinase receptor is divided into different domains: a unique domain, an SH3 domain, an SH2 domain, a protein tyrosine kinase domain, and a regulatory tail, which runs from the N-terminus to the C-terminus. Src kinase inhibitors bind in the kinase domain and are activated by phosphorylation. The etiology of cancer involved various signaling pathways and Src signaling pathways are also involved in those clusters. Although the dysregulation of Src kinase resulted in cancer being discovered in the late 19th century it is still considered a cult pathway because it is not much explored by different medicinal chemists and oncologists. The Src kinase regulated through different kinase pathways (MAPK, PI3K/Akt/mTOR, JAK/STAT3, Hippo kinase, PEAK1, and Rho/ROCK pathways) and proceeded downstream signaling to conduct cell proliferation, angiogenesis, migration, invasion, and metastasis of cancer cells. There are numerous FDA-approved drugs flooded the market but still, there is a huge demand for the creation of novel anticancer drugs. As the existing drugs are accompanied by several adverse effects and drug resistance due to rapid mutation in proteins. In this review, we have elaborated about the structure and activation of Src kinase, as well as the development of Src kinase inhibitors. Our group also provided a comprehensive overview of Src inhibitors throughout the last two decades, including their biological activity, structure-activity relationship, and Src kinase selectivity. The Src binding pocket has been investigated in detail to better comprehend the interaction of Src inhibitors with amino acid residues. We have strengthened the literature with our contribution in terms of molecular docking and ADMET studies of top compounds. We hope that the current analysis will be a useful resource for researchers and provide glimpse of direction toward the design and development of more specific, selective, and potent Src kinase inhibitors.

Explanatory review on pyrimidine/fused pyrimidine derivatives as anticancer agents targeting Src kinase.

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.

An assessment of EGFR and HER2 inhibitors with structure activity relationship of fused pyrimidine derivatives for breast cancer: a brief review.

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.

An outlook of docking analysis and structure-activity relationship of pyrimidine-based analogues as EGFR inhibitors against non-small cell lung cancer (NSCLC).

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.