This new article publication from Acta Pharmaceutica Sinica B, discusses DHL-11, a novel prieurianin-type limonoid isolated from Munronia henryi, targeting IMPDH2 to inhibit triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterised by the poorest prognosis, and poses a significant threat to women's health.

In this study two novel prieurianin-type limonoids extracted from Munronia henryi were identified, one of which, named DHL-11, exhibited antitumor activity against TNBC cells.

DHL-11 suppressed cell proliferation and migration, induced G2/M cell cycle arrest and apoptosis, and effectively increased the accumulation of reactive oxygen species (ROS) and cellular DNA damage in TNBC cells.

Mechanistically, it was found that DHL-11 binds to the non-catalytic pocket of IMPDH2 and disrupts the interaction between IMPDH2 and FANCI, leading to the degradation of the IMPDH2 protein.

The decrease of IMPDH2 protein reduced guanine synthesis, increased ROS levels, and induced DNA damage.

DHL-11 significantly inhibited the growth of breast cancer patient-derived organoids with high IMPDH2 expression.

Furthermore, DHL-11 inhibited the growth and metastasis of TNBC xenografts in vivo with favourable biosafety profiles.

These findings highlight the potential of DHL-11 as a novel IMPDH2 degrader for the treatment of IMPDH2-positive TNBC.

Keywords: Limonoids, DHL-11, TNBC, ROS, DNA damage, IMPDH2, Guanine, FANCI

Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383525007099-ga1_lrg.jpg

DHL-11 competes with FANCI to bind IMPDH2, destabilising it, reducing GMP synthesis, causing DNA damage and replication stress, and inducing TNBC cell apoptosis.

The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association.

Source: Compuscript Ltd