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As a key mediator of tumor angiogenesis, VEGFR-2 has emerged as a promising therapeutic target for combating cancer. In the present study, a series of 6-substituted-3-(4-(4-(substitutedphenyl/benzyl)piperazin-1-yl)benzylidene) indolin-2-one derivatives (2-24) were synthesized in good yields and structurally confirmed by IR, NMR, and HRMS analyses. Several compounds exhibited strong VEGFR-2 inhibition, with activities comparable to or exceeding that of sorafenib, but lower than sunitinib. Cytotoxicity assays against MCF-7 breast cancer cells revealed five derivatives (4, 7, 9, 10, and 12) more active than doxorubicin along with five additional compounds showing comparable potency. In contrast, the compounds displayed moderate cytotoxic activity against the MDA-MB-231 cell line and none showed significant toxicity toward MCF-10A  normal breast epithelial cells. Mechanistic studies of compound 10 demonstrated G0/G1 phase arrest, apoptosis induction, and increased ROS generation, suggesting its potential as a selective and effective lead for breast cancer therapy.

Phenyl amino pyrimidine (PAP) derivatives represent a promising scaffold in anticancer drug discovery due to their potential to selectively inhibit tyrosine kinase (TK) enzymes implicated in tumor progression. In the present study, we designed a focused ligand library using bioisosteric substitutions in the imatinib structure to improve its target affinity and pharmacokinetic properties. Molecular docking confirmed the high-affinity of the designed compounds against the human proto-oncogene tyrosine-protein kinase ABL1 (PDB ID: 2hyy), and eight potential leads were synthesized based upon their key interactions within the target's ATP-binding pocket. The synthetic routes for these molecules followed a robust multi-step protocol, yielding pure compounds characterized comprehensively by NMR, HRMS, and chromatographic analyses, confirming structural integrity and purity. Cellular cytotoxicity assays demonstrated potent antiproliferative effects of these derivatives against DLD-1, HCT-116, and HT-29 colorectal cancer cell lines, exhibiting superior efficacy and selectivity (SI) compared to the benchmark drug imatinib mesylate (IC50 = 18.3 μM; SI = 1.36). Based on docking score and experimental outcome in cell viability assays, two lead compounds DS37 (IC50 = 3.11 μM; SI > 16) and DS42 (IC50 = 11.9 μM; SI > 16.8) were selected for further validation through 100 ns molecular dynamics simulations for their mechanistic establishment with ABL1. These studies confirmed their stable binding modes and dynamic conformational compatibility with the TK active site.

SET domain-containing protein 2 (SETD2) is the only methyltransferase that catalyzes the trimethylation of lysine at position 36 of histone H3 (H3K36me3), playing a vital role in correcting base mismatches and repairing DNA damage during gene replication and transcription. Therefore, it ensures the stability of the genome. The AWS-SET-PostSET domains within SETD2 play a pivotal role in gene mismatch repair, regulating cellular differentiation and apoptosis. However, mutations frequently occur in the AWS-SET-PostSET domains, leading to abnormal expression of H3K36me3 and promoting tumorigenesis and disease progression. Therefore, SETD2 has emerged as a significant target for clinical diagnosis and cancer therapy. This article introduces the domains and functions of the SETD2 protein, further elucidating its role in the initiation and development of cancer. It explores the roles and differences of SETD2 and its family proteins in cancer. Additionally, the article elucidates existing SETD2 inhibitors, introduces two important inhibitor core structures (methylindole scaffold and sinefungin analogs), and summarizes their structure-activity relationships (SARs). This review outlines the structural mechanisms by which inhibitors target SETD2, highlighting interactions with specific amino acids. By analyzing the SARs of inhibitors, we provide recommendations for drug design targeting SETD2 inhibitors, emphasizing the importance of the rigid chair conformation of the cyclohexyl structure to binding. This review aims to serve as a reference for the development of novel SETD2 inhibitors.

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small-cell lung cancer (NSCLC) accounting for approximately 85% of all cases. Despite widespread use, the limited durability of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) highlights the need for strategies that suppress tumour proliferation and restore apoptosis in resistant NSCLC. In this study, a series of eleven 2-anilinoquinazoline derivatives was synthesised to identify new scaffolds capable of restoring apoptotic signalling in drug-resistant NSCLC cells. Among these, JS04 emerged as the most potent derivative, exhibiting antiproliferative activity with IC₅₀ values of 8.11 ± 0.43 μM and 11.58 ± 1.68 μM against H1975 (EGFR-TKI resistant) and A549 (EGFR-independent) cell lines, respectively, outperforming gefitinib. Real-time impedance (xCELLigence) and flow cytometry analyses demonstrated that JS04 induced rapid, dose-dependent apoptosis, achieving 74% apoptotic cell death at 20 μM, substantially higher than erlotinib (13%). Proteome profiling confirmed activation of both intrinsic (downregulation of Bcl-2, Bcl-xL, and survivin) and extrinsic (upregulation of TRAIL R2/D5) apoptotic pathways, accompanied by G₂/M phase cell cycle arrest comparable to osimertinib. Zebrafish embryo assays revealed a favourable safety profile (LC₅₀ = 38.42 ± 3.96 μM). Computational studies, molecular docking and 100 ns molecular dynamics simulations indicated that JS04 forms stable hydrogen bonds with hinge region residues MET793 and GLN791, and exhibits strong binding affinity toward the EGFRL858R/T790M kinase. Collectively, these findings position JS04 as a promising quinazoline-based lead candidate that effectively triggers dual apoptotic mechanisms, selectivity toward H1975 cells, and demonstrates early indications of safety, warranting further biochemical validation, structure-activity optimisation, and in vivo efficacy evaluation.

Cancer remains a major global health challenge, and the development of new therapeutic agents is urgently needed to overcome poor selectivity and multi-drug resistance. Targeting DNA replication enzymes such as topoisomerase I (Topo I), which regulates DNA topology during replication and transcription, represents an effective chemotherapeutic strategy. This study aimed to design and synthesize new benzothiophene and benzothienopyran derivatives as potential Topo I inhibitors with additional immunomodulatory activity. Four series of derivatives including benzothiophene (2a-c) and benzo[4,5]thieno[3,2-b]pyran (3a-c, 4a-c, and 5a-c) were synthesized, characterized, and biologically evaluated. In vitro cytotoxicity screening against the NCI-60 cancer cell panel demonstrated broad and potent activity, with several compounds showing 70 to >100% growth inhibition. The most active derivatives were further assessed in a five-dose NCI assay and a DNA relaxation assay for Topo I inhibition. Compounds 2c and 5c exhibited superior Topo I inhibition (IC50 = 17.69 ± 0.6 μM and 18.79 ± 0.64 μM, respectively) compared with topotecan (IC50 = 27.27 ± 0.93 μM) and showed higher selectivity toward cancer cells over PCS-800-017 normal cells. Both compounds induced G0/G1 cell cycle arrest and apoptosis in SR leukemia cells. Notably, compound 5c activated the cGAS-STING pathway and modulated apoptosis-related markers. Molecular docking studies rationalized the superior Topo I inhibitory potential of compound 5cvia forming strong interaction with the Topo I-DNA complex. Molecular dynamics (MD) simulation studies demonstrated remarkable positional stability of compound 5c with no significant structural perturbations in the Topo I active site. Additionally, drug-likeness and pharmacokinetic properties, predicted by SwissADME, indicated that 5c complies with Lipinski's and Veber's rules of oral bioavailability showing a bioavailability score of 0.55. These findings highlight compound 5c as a promising Topo I inhibitor with mechanistically validated multimodal anticancer activity, superior inhibitory potency compared with topotecan, and enhanced selectivity toward cancer cells over normal CD8+ cells, supporting its potential for further anticancer drug development.

The combination of PARP1 and CDK6 inhibitors shows synergistic anticancer effects in TNBC. However, first-generation PARP inhibitors lack optimal PARP trapping efficiency and enzyme family selectivity, often leading to hematotoxicity. Herein, we report the rational design and synthesis of a series of second-generation selective PARP1/CDK6 dual inhibitors, based on the structural features of the latest selective PARP1 inhibitor AZD5305. Among these, PC8 exhibits potent dual inhibition of PARP1 (IC50 = 0.126 μM) and CDK6 (IC50 = 0.197 μM), showing selectivity over PARP2 (IC50 = 0.824 μM). PC8 effectively inhibits the proliferation and migration of TNBC cells, and induces intracellular ROS accumulation, thereby exacerbating mitochondrial dysfunction and DNA damage. Additionally, it modulates the classical Wnt signaling pathway. Furthermore, compared with first-generation inhibitors, PC8 displays improved metabolic stability in liver microsomes. As a novel selective PARP1/CDK6 dual inhibitor with improved pharmacological properties, PC8 represents a promising lead structure for further optimization of second-generation PARP1/CDK6 dual inhibitors for the treatment of TNBC.

Cancer remains one of the most significant health challenges worldwide. Despite the continuous development of anticancer drugs, the battle against cancer persists due to frequent mutations. Tropomyosin receptor kinase A (TrkA) is considered one of the promising targets in cancer therapy. The urge to overcome drug resistance has prioritized the need for synthesizing potent TrkA inhibitors. In this study, we synthesized a series of sixteen novel pyrimidinone derivatives that showed potent activity against the TrkA enzyme using sequential chemical reactions. The targeted compounds were screened in vitro using an MTT assay against three cell lines, including HepG2, MCF-7, and K-562. Some of the screened compounds exhibited good antitumor activity, such as compound 6m, which showed more potent activity against the MCF-7 cell line, with an IC50 of 19.1 μM, compared to 24.2 μM for 5-fluorouracil, a reference drug. Furthermore, cell cycle and apoptosis assays were performed to confirm the induction of cell cycle arrest in the G1 phase in addition to their potent antiproliferative effects. In addition, an enzyme inhibition assay was performed for all prepared compounds against the TrkA enzyme. Compounds 6b, 6i, 6j, and 6n exhibited the most preferable activity, with IC50 values of 8.9, 8.9, 8.0, and 6.6 μM, respectively, compared to Sorafenib (IC50 = 0.6 μM), serving as a control drug. Moreover, in silico computational studies, such as molecular docking and ADME predictions, were done to predict the ligand-protein interactions, physicochemical properties, and oral bioavailability of the proposed compounds.

Lung cancer remains one of the leading causes of cancer-related mortality worldwide, and dysregulation of the epidermal growth factor receptor (EGFR) signaling pathway plays a central role in its progression. In the present study, a novel series of fused isoxazole and fused 1,2,3-triazole derivatives (4a-4 h and 5a-5 h) were rationally designed, synthesized and evaluated for their anticancer potential against human lung cancer cells. These compounds were synthesized via a single-step [3 + 2] cycloaddition reaction using (Z)-1-(4-fluorophenyl)-N-(4-iodobut-3-yn-2-ylidene)-3-methyl-1H-pyrazol-5-amine as the key precursor. In silico molecular docking studies revealed strong and stable interactions of the synthesized compounds with the ATP-binding pocket of the EGFR kinase domain, comparable to that of the reference drug, erlotinib. In vitro EGFR kinase inhibition assays confirmed the ability of the lead compounds to suppress kinase activity. Cytotoxicity studies on non-cancerous cell lines (HBEC30KT and HEK293) demonstrated minimal toxicity and a favorable therapeutic window.In contrast, selected compounds, particularly 4 h, 5d and 5 h, exhibited potent antiproliferative activity in lung cancer cell lines H1975 and A549, with a marked reduction in cell viability and growth. Flow cytometric analysis revealed significant cell cycle arrest in the Sub-G1 phase, accompanied by induction of apoptosis as confirmed by Annexin V-FITC staining. Furthermore, Transwell migration and soft agar colony formation assays demonstrated a strong inhibitory effect on cancer cell migration and anchorage-independent growth, indicating effective suppression of metastatic and tumorigenic potential. In silico Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis predicted favorable pharmacokinetic and safety profiles for the lead compounds.Collectively, the results suggest that fused isoxazole and fused 1,2,3-triazole derivatives, especially compounds 4 h, 5d and 5 h, represent promising lead molecules for the development of novel EGFR-targeted therapies for lung cancer. Further in vivo studies and detailed pharmacological investigations are warranted to validate their therapeutic potential.

Glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis, has emerged as a compelling therapeutic target for colorectal cancer (CRC). Capitalizing on the therapeutic promise of this target, we rationally designed and synthesized 24 novel Artesunate-Ebselen (ART-EBS) derivatives through structure-activity relationship (SAR) studies. Among these analogs, compound 5k exhibited the most potent antiproliferative activity against HCT116 cells with an IC₅₀ value of 0.81 ± 0.29 μM, thereby significantly outperforming its parent compounds ART (IC₅₀ > 50 μM) and EBS (IC₅₀ > 50 μM). Mechanistic investigations revealed that compound 5k triggered lipid peroxidation through the accumulation of reactive oxygen species (ROS). This was supported by multiple lines of evidence, including markedly increased ROS production, disrupted mitochondrial membrane potential, and downregulated GPX4 expression-ultimately culminating in ferroptosis of HCT116 cells. A cellular thermal shift assay (CETSA) further confirmed that compound 5k could directly bind to GPX4 protein and enhance its stability under increasing temperature, providing robust in situ evidence for the specific interaction between compound 5k and GPX4. In the CT26 xenograft model, compound 5k exerted robust tumor growth-inhibitory effects, achieving a tumor inhibition rate (TIR) of 54.9%-substantially higher than the 28.9% observed in the ART monotherapy group-without inducing significant body weight loss in mice. In contrast, all mice in the ART + compound 3k (the ebselen-based parent scaffold of compound 5k) combination group died within 24 h as a result of severe systemic toxicity. Flow cytometry analysis of immune cells in tumor-bearing mice showed that compound 5k significantly increased the proportion of CD4+ T cells in the spleen (6.2% vs. 3.5% in the control group) and promoted the infiltration of CD8+ cytotoxic T cells into tumor tissues (7.2% vs. 0.9% in the control group), indicating activation of the antitumor immune response. These findings collectively indicate that compound 5k exerts synergistic anti-CRC efficacy by triggering ferroptosis and activating antitumor immunity. Thus, compound 5k holds considerable promise as a lead ferroptosis inducer for the development of novel CRC therapeutic strategies.

Gossypol is a polyphenolic compound recognized for its role as a Bcl-2 family protein inhibitor, attracting considerable interest mainly due to its antitumor properties. However, its development as a therapeutic agent has faced hurdles from off-target side effects, partially stemming from an incomplete understanding of its target profile. In this study, we identified Gossypol as a multi-deubiquitinating enzyme (DUB) inhibitor, exhibiting preference for the ubiquitin-specific protease (USP) subfamily members. Gossypol demonstrated IC50 values ranging from 0.30 μM to 4.97 μM against USP2 CD, USP7 CD, USP8 CD, USP28 CD and USP9X CD. Mechanistic studies, including 1D NMR, IC50 shift assays, fluorescence quenching experiments, and enzymatic reversibility tests revealed that Gossypol mainly acts as non-covalent inhibitor against multiple DUBs, with binding affinities towards representative USPs between 10 and 30 μM. Cell-based assays confirmed Gossypol's efficacy in inhibiting intracellular DUB activity, leading to increased ubiquitination levels. Moreover, Gossypol exhibited cytotoxic effects on human breast, prostate, and colorectal cancer cell lines, at least partially through downregulating the oncogenic substrates of targeted DUBs such as c-Myc, Mcl-1, MDM2, and Cyclin D1. Collectively, our findings position Gossypol as a promising small-molecule inhibitor targeting DUBs, especially USPs, and provide a rationale for further exploring its therapeutic potential in USP-driven cancers.