NQO1-Responsive Prodrug for <i>in Cellulo</i> Release of Cytochalasin B as Cancer Cell-Targeted Migrastatic

Mervic D. Kagho; Katharina Schmidt; Christopher Lambert; Lili Jia; Vignesh Venkatakrishnan; Luisa Mehr; Johan Bylund; Klemens Rottner; Marc Stadler; Theresia E. B. Stradal; Philipp Klahn

doi:10.1002/smll.202410861

NQO1-Responsive Prodrug for in Cellulo Release of Cytochalasin B as Cancer Cell-Targeted Migrastatic
Journal article, 2025

Migrastatic drugs targeting cell motility and suppressing invasiveness of solid tumors, have the potential to bring about a paradigm shift in the treatment of solid cancer. Cytochalasin B (CB) is a potent migrastatic compound, but its clinical use is limited by poor selectivity. Here, a NQO1-responsive prodrug, BQTML-CB is developed, synthesized in three steps from cytochalasin B derived from Preussia similis G22. BQTML-CB is selectively activated in NQO1-positive cancer cells, releasing active CB. In vitro, BQTML-CB significantly inhibits proliferation and migration in NQO1-positive U-2OS cells, causing actin disruption and cytokinesis abnormalities, while sparing NQO1-negative B16-F1 cells. The prodrug shows reduced effects on human neutrophils, indicating reduced immunosuppressive activity of BQTML-CB compared to CB. Co-culture studies reveal a beneficial bystander effect, as cleaved CB diffused into adjacent NQO1-deficient cells. These findings support BQTML-CB as a cancer-targeted prodrug with selective antiproliferative and migrastatic properties, highlighting the potential of C7-OH-modified cytochalasans in cancer therapy.

prodrugs

NQO1

cytochalasin B

migrastatics