Discovery of novel stachybenzals, as covalent asparagine synthetase inhibitors

July 11, 2025

For the development of anti-cancer agents targeting cancer metabolism

A collaborative research group including scientists from Kyoto University, Tokyo University of Science, RIKEN CSRS, and Keio University has identified a new class of covalent inhibitors of asparagine synthetase (ASNS), named stachybenzals A–C. These compounds are produced by filamentous fungi of the genus Stachybotrys and have demonstrated potential as lead compounds for anti-cancer drugs targeting non-small cell lung cancer.

ASNS is known to be highly expressed in several cancers, including lung cancer, colorectal cancer, and acute lymphoblastic leukemia. It is implicated a key enzyme that promotes cancer progression, recurrence, and resistance to chemotherapy. To facilitate the development of covalent ASNS inhibitors, the research group established a simple and highly sensitive evaluation system using the lysine-mimicking compound N-Boc-L-Lys. Through this system, they discovered the meroterpenoid compounds stachybenzals A–C, which covalently bind to the lysine residue at position 556 of ASNS, thereby inhibiting its enzymatic activity and exhibiting anti-cancer effects. These compounds exhibited notable anti-cancer activity, suggesting their potential as novel therapeutic agents targeting cancer-specific metabolic pathways.

 

Original article

Journal of Natural Products　doi: 10.1021/acs.jnatprod.5c00572

L. Zhang, H. Uekusa, T. Suzuki, N. Dohmae, A. Hattori, Y. Hirano, H. Kakeya,

"Natural Lysine-reactive Meroterpenoids, Stachybenzals A-C, as Covalent Asparagine Synthetase Inhibitors".

Contact

Naoshi Dohmae
Unit Leader
Biomolecular Characterization Unit