Novel Selenium-Containing Small Molecule PD-L1 Inhibitors: Design, Synthesis, and Evaluation of the Antitumor Activity.

Rational design and biological validation of EZH2/PD-L1 bifunctional inhibitors for colorectal cancer immunotherapy

PE-1 demonstrates dual-target inhibitory activity against the PD-1/PD-L1 immune checkpoint and EZH2, underscoring its potential as a lead compound for the development of next-generation bifunctional anticancer agents.

Dual-targeting CD73/PD-L1 bifunctional inhibitor: a promising cancer immunotherapy strategy

CP-1 exhibits balanced, dual-nanomolar inhibitory activity against PD-L1 and CD73 and displays potent immunomodulatory effects at the cellular level and serves as a promising lead candidate for developing novel bifunctional agents to advance tumor immunotherapy.

Design, synthesis, and anti-prostate cancer activity evaluation of novel thieno[2,3-b]pyridine derivatives as potential BLM helicase inhibitors.

Discovery of novel hydroxycamptothecin derivatives as potent Topo I inhibitors for antitumor guided by molecular dynamics.

Camptothecin (CPT) and its derivatives are clinically validated topoisomerase I (Topo I) inhibitors with broad-spectrum antitumor activity. Based on the stabilization of the covalent DNA-Topo I complex, modification at the 10-position of the CPT scaffold represents a promising strategy to enhance binding affinity. Herein, the rational design, synthesis, and biological evaluation of novel 10-substituted CPT derivatives guided by molecular dynamics (MD) simulations are presented. A total of 45 derivatives were synthesized and evaluated for their antiproliferative activity against three human cancer cell lines (A549, HCT116, HepG2). Structure-activity relationship (SAR) studies demonstrated that the carbonylmethylene linker and 3-methoxy-4-methylphenyl substitution afforded optimal potency. The most promising compound C6 showed exceptional cytotoxicity against HCT116 cells with an IC50 value of 0.001 μM, 16-fold more potent than that of compound SN-38. Mechanistic studies confirmed that C6 induced S-phase cell cycle arrest and apoptosis in HCT116 cells, suppressed cell migration and invasion, and downregulated Topo I protein expression in a concentration-dependent fashion. Furthermore, compound C6 exhibited significant in vivo antitumor efficacy in an HCT116 xenograft model with a favorable safety profile. Pharmacokinetic evaluation in rats confirmed moderate absolute bioavailability and a reasonable half-life. Collectively, compound C6 was identified as a potent Topo I inhibitor with promising antitumor activity.

Design and Synthesis of 2,4-Thiazolidinedione-Based Derivatives as Potent EGFR-Targeting Anticancer Agents

A series of quinoline- and naphthalene-based 2,4-thiazolidinedione (TZD) hybrids (5a–5o) were rationally designed and synthesized using a pharmacophore hybridization approach targeting epidermal growth factor receptor (EGFR). The synthesized compounds were evaluated for in vitro antiproliferative activity against human cancer cell lines including MDA-MB-453, A549, PC-3, and MCF-7, along with EGFR inhibitory activity. Several compounds exhibited promising cytotoxicity, with derivatives 5c, 5f, 5g, and 5n showing significant activity (IC₅₀ = 4.6–9.8 µM). Molecular docking studies using EGFR crystal structures (PDB: 1M17 and 4HJO) demonstrated favorable binding affinities and key interactions with the ATP-binding pocket, particularly hydrogen bonding with Met793. Docking results correlated well with experimental EGFR inhibition, supporting an EGFR-mediated mechanism. Structure–activity relationship analysis revealed the importance of the TZD core, electron-rich aromatic moieties, and balanced lipophilicity for enhanced anticancer activity. These findings identify TZD hybrids as promising EGFR-targeted anticancer leads.

Discovery of a novel 1H-pyrazole-3-amine derivative 6h with potent antitumor activity by targeting tubulin and FLT3.

A novel series of 1H-pyrazole-3-amine derivatives was designed, synthesized, and their antitumor activities were evaluated. Among them, 6h showed potent antiproliferative activity against solid tumor cell lines and leukemia cell lines, with IC50 values ranging from 3.3 to 25.0 nM. Mechanism studies revealed that 6h could effectively inhibit microtubule polymerization (IC50 = 3.6 μM) via targeting the colchicine binding site and disrupted cellular microtubule networks. Notably, the preliminary kinase selectivity results showed 6h displayed selectivity for FLT3 kinase (IC50 = 58.6 nM) over other kinases screened, including the homologous c-KIT. Western blot analysis demonstrated that 6h inhibited the phosphorylation of FLT3 and its downstream signaling mediator STAT5 in MOLM-13 cells. 6h could induce tumor cell cycle arrest and apoptosis. Furthermore, in a MOLM-13 xenograft model, 6h at the dosage of 30 mg/kg exhibited effective antitumor activity without notable body-weight loss and the major organ damage. Pharmacokinetic evaluation of 6h in rats revealed an oral bioavailability of 5.6 %. Molecular docking and dynamics simulations supported stable binding modes of 6h with both tubulin and FLT3. Collectively, these results suggested that 6h could be regarded as a promising lead compound against tubulin and FLT3 for further investigation.