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.

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.

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.

(R)-A17, a novel, highly selective PARP1 inhibitor featuring a unique tricyclic scaffold, is developed and established as a promising candidate and the design strategy for the next-generation PARP1-targeted therapy is validated.

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

A one‐pot synthesis of aromatic aminopropyl lactams (ArAPLs) via hydrolysis of bicyclic amidines (DBN, DBU), followed by reductive amination with aromatic aldehydes supports the cytotoxic potential of ArAPLs.