Journal of Medicinal Chemistry最新文献

While cationic antimicrobial peptides (AMPs) are extensively studied for antitumor effects, anionic AMPs remain underexplored. Notably, no amphibian-derived anionic cathelicidins with antitumor activity have been reported. This study identifies Boma-CATH, a novel anionic cathelicidin (net charge–3) from Bombina maxima skin, which suppresses melanoma growth in mice and triggers pyroptosis-like morphological changes in A375 cells via the NLRP3/Caspase-1/GSDMD pathway. Further investigation revealed that ROS played a crucial role in promoting pyroptosis, as NAC (ROS scavenger) and Ac-YVAD-cmk (Caspase-1 inhibitor) reversed cell death and reduced LDH/IL-1β release in vitro and in vivo. GSDMD knockdown further validated its role. Additionally, Boma-CATH inhibited A375 cell proliferation, migration, and invasion, demonstrating dual antitumor mechanisms: pyroptosis induction and metastasis suppression. Importantly, Boma-CATH caused no adverse effects in mice, highlighting its therapeutic safety. These findings position Boma-CATH as a promising melanoma treatment and expand the mechanistic understanding of anionic AMPs in oncology.

Galectins play significant roles in regulating immune responses, posing challenges for cancer immunotherapy. The development of galectin inhibitors has been limited by their high structural homology and the lack of noninvasive imaging tools to identify potential responsive patients. We developed 12 galectin-7-specific inhibitors using nanobodies (Nbs) and identified G7N8 as the lead Nb. G7N8 was conjugated with the NOTA chelator, labeled with copper-64 ([⁶⁴Cu]Cu), and used as a radiotracer for PET imaging in a triple-negative breast cancer (TNBC) mouse model. Nbs demonstrated high affinity for galectin-7, with no binding activity for other galectins tested. The lead Nbs inhibited galectin-7 binding to T-cell glycoreceptors and reduced subsequent apoptosis. PET imaging with [⁶⁴Cu]Cu-NOTA-G7N8 showed selective radiotracer accumulation at 20 h (P = 0.001). We developed galectin-7-specific Nbs that inhibit T-cell apoptosis and enable PET imaging of TNBC, providing novel tools for investigating immune regulation and enhancing cancer immunotherapy.

A library of potent WEE1 kinase inhibitors was synthesized based on the discontinued frontrunner clinical candidate AZD1775 (1), many of which were more selective for WEE1 over an undesirable off-target of 1, the kinase PLK1. When tested against patient-derived organoids (PDOs) grown from TP53-mutated colorectal cancer (CRC) peritoneal metastases, 34 (IC₅₀ value of 62 nM) exhibited stronger efficacy than 1 (IC₅₀ value of 120 nM) and the best-in-class clinical candidate ZN-c3 (IC₅₀ value of 127 nM). Against primary CRC PDOs with TP53-WT, 34 significantly enhanced DNA damage, replication stress and apoptosis compared to 1, as well as demonstrated high selectivity over patient-matched normal healthy colon PDOs, highlighting a potential therapeutic window for cancer treatment. Overall, this investigation provides critical insight into several potent WEE1 inhibitors that exhibited exceptional efficacy against CRC PDOs and is the first to utilize a PDO platform to assess their effect on healthy and malignant cell viability.

The α7 nicotinic acetylcholine receptors (nAChRs), identified in peripheral and central nervous systems, are crucial for cognitive function, memory, inflammation, and are linked to disorders like Alzheimer’s disease (AD), lung cancer, myasthenia gravis, and atherosclerosis. Here we report that a novel α4/7-conotoxin (CTx) LvID, from Conus lividus, potently inhibits rat α7 nAChRs expressed in Xenopus oocytes with an IC₅₀ of 13.8 nM, showing little activity against other rat nAChR subtypes. The structure of LvID was elucidated using nuclear magnetic resonance (NMR) spectroscopy and comprises a short helix braced by disulfide bonds. The key residues of LvID that bind to the α7 nAChRs were determined from a series of alanine mutants. Molecular simulation provided a possible explanation for the activity and specificity of LvID binding to α7 nAChRs. This finding offers a vital pharmacological tool for investigating the structural features and functional mechanisms of α7 nAChRs.