3-amino-1,2,4-triazine scaffolds as next-generation PDK inhibitors: Design, mechanistic insights, and efficacy in pancreatic ductal adenocarcinoma.

Design, synthesis and evaluation of benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one derivatives as novel MTA cooperative PRMT5 inhibitors for the treatment of MTAP-deleted cancers.

Protein arginine methyltransferase 5 (PRMT5) has emerged as a promising therapeutic target due to its critical roles in regulating fundamental cellular processes such as proliferation, migration, and differentiation. Although several PRMT5 inhibitors have been reported, but none have gained clinical approval. Herein, we describe the discovery of a novel series of benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ones derivatives as MTA cooperative PRMT5 inhibitors. Compound 9u exhibited significant antiproliferative activity in MTAP-deleted HCT116 cancer cells, with an IC50 value of 13 nM, exhibiting 70-fold selectivity over MTAP wild type HCT116 cells. Furthermore, 9u displayed robust efficacy across diverse MTAP-deleted cancer cell lines, achieving IC50 values of <1.5-51 nM. Notably, it also showed favorable metabolic stability in both human and mouse liver microsomes. These findings establish a promising lead for the development of PRMT5-MTA inhibitors specifically targeting MTAP-deficient cancers.

Recent advances in 1,3,5-triazine-based PI3K inhibitors for cancer therapy: a comprehensive review.

Dysregulation of the phosphatidylinositol-3-kinase (PI3K) - AKT/mTOR signaling axis is a major molecular driver of tumor initiation, progression, and therapeutic resistance across diverse cancers, underscoring the need for improved targeted therapies amid a rising global and Indian cancer burden. This comprehensive review critically summarizes advances from 2021-2025 in the design of selective PI3K inhibitors based on the 1,3,5-triazine (s-triazine) scaffold, emphasizing how its symmetric 2/4/6 substitution vectors, electron-deficient hinge-binding profile, and modular cyanuric chloride - enabled SNAr synthesis accelerate structure - activity relationship (SAR) optimization. Medicinal chemistry and biological evidence across multiple triazine chemotypes (benzoyl-hydrazide, thiophene/thiophenyl-arylurea, aminopyrimidine, dimorpholinyl, benzimidazole, phenylamino, and pyrazolyl derivatives) reveal convergent design rules: heteroaryl/aminopyrimidine hinge binders, pocket-filling hydrophobic arms, and solvent-exposed polar groups (notably morpholine/dimorpholine or sulfonyl piperazine) collectively improve potency, isoform selectivity, and cellular efficacy. Mechanistically, representative compounds induce G0/G1 arrest and apoptosis with suppression of p-PI3K/p-AKT and downstream markers, supported by docking/MD interactions frequently involving Val851 (hinge), Asp810, Lys802, and Gln859. Despite substantial progress, pharmacokinetic liabilities, resistance pathways, and isoform-associated adverse effects remain key barriers to translation. Future development should prioritize rational isoform targeting, hybrid/multitarget designs, systematic ADME refinement, and AI-driven SAR modeling to advance s-triazine PI3K inhibitors toward clinically feasible cancer therapeutics.

Discovery, Synthesis, and Biological Evaluation of 1,3,4,5-Tetrahydro-6H-pyrano[4,3-c]isoquinolin-6-one Derivatives as Novel and Highly Selective PARP1 Inhibitors.

Developing highly selective PARP1 inhibitors is a promising strategy to improve the therapeutic window compared with dual PARP1/2 inhibitors. Through structure-guided design and optimization, we developed (R)-A17, a novel, highly selective PARP1 inhibitor featuring a unique tricyclic scaffold. It demonstrates nanomolar enzymatic potency (PARP1 IC50 = 2.4 nM), exceptional 65.8-fold selectivity over PARP2, and robust antiproliferative activity in BRCA-deficient cells. (R)-A17 exhibits favorable pharmacokinetic properties with complete oral bioavailability (F = 100%) in mice. Mechanistically, it selectively inhibits PARP1-mediated PARylation and induces DNA damage and G2/M phase arrest. In vivo, oral administration of (R)-A17 produced dose-dependent antitumor efficacy in BRCA mutant xenograft models, achieving tumor growth inhibition values of 57.8, 86.3, and 91.3% at doses of 0.3, 1, and 3 mg/kg, respectively, while also synergizing effectively with liposomal irinotecan in an HCT116 xenograft model. These results establish (R)-A17 as a promising candidate and validate the design strategy for the next-generation PARP1-targeted therapy.

Novel benzofuran-1,3,4-thiadiazole aryl urea hybrids as dual VEGFR-2/BRAF inhibitors: anticancer activity, apoptosis induction, and molecular modeling studies.

The development of dual-directed anticancer agents has emerged as an effective strategy to simultaneously modulate tumor proliferation and angiogenesis while overcoming resistance associated with single-target therapies. In the present study, a novel series of benzofuran-based aryl urea derivatives incorporating a 1,3,4-thiadiazole linker were designed as dual VEGFR-2/BRAFWT inhibitors using sorafenib as a pharmacophoric template. The in vitro cytotoxic activity of the synthesized compounds against cervix HeLa, prostate PC-3, colon HCT-116, and breast MCF-7 cancer cell lines was evaluated. Most derivatives showed variable activity, with 5-bromobenzofuran analogues displaying superior potency. Compound 7j emerged as the most active analogue, with IC50 values of 7.83-13.27 μM and reduced toxicity toward normal lung fibroblast WI-38 cells. Enzymatic assays revealed potent dual inhibition of VEGFR-2 and BRAFWT by 7j (IC50 = 0.044 and 0.071 μM, respectively), outperforming sorafenib and vemurafenib. Mechanistic studies showed that 7j induced G2/M cell cycle arrest and promoted apoptosis in HeLa cells. This effect was associated with upregulation of BAX, p53, and caspase-9, downregulation of Bcl-2, and activation of the intrinsic apoptotic pathway. Additionally, in silico studies including molecular docking and molecular dynamics simulations demonstrated stable ligand-target interactions and favorable binding modes of 7j across both VEGFR-2 and BRAF, supporting the proposed hybrid design strategy. Overall, compound 7j represents a promising dual VEGFR-2/BRAFWT inhibitor and highlights benzofuran-based scaffolds as valuable platforms for anticancer drug development.

Tetrazole–imidazole hybrid derivatives as potential EGFR tyrosine kinase inhibitors: design, synthesis and in silico evaluation with preliminary antiproliferative assessment

Synthesis and Biological Activity of Novel Aromatic Aminopropyl Lactams in Two Cancer Cell Models

The development of new therapeutic agents for glioblastoma and hepatocellular carcinoma (HCC) remains a priority due to poor prognosis, limited treatment options, and high recurrence rates. Herein, we report a one‐pot synthesis of aromatic aminopropyl lactams (ArAPLs) via hydrolysis of bicyclic amidines (DBN, DBU), followed by reductive amination with aromatic aldehydes. These compounds were designed to target histamine H3 receptors (H3R), which are often overexpressed in these malignancies. Docking studies suggested that compounds 3a and 4a may act as H3R antagonists, showing favorable binding through hydrophobic and hydrogen‐bonding interactions. Biological evaluation identified 3a and 4a as the most promising compounds, exhibiting micromolar antiproliferative activity in glioblastoma and HCC cell models. Compound 3a showed the best balance between potency and selectivity, including activity in 3D spheroid models and modulation of cell cycle‐related markers. In coculture systems, spheroids displayed reduced size and density, although a slight increase in viability was observed, particularly with 4a. Variations in peripheral cell layers suggest a role for macrophage behavior. Overall, these findings support the cytotoxic potential of ArAPLs, although further studies are required to confirm their role as H3R antagonists.