Benzofused carboxamide D13 combines PARP inhibition and tubulin colchicine-site binding, showing strong antitumor activity in cells and a breast cancer xenograft
- Benzofused heterocyclic carboxamides were designed as single molecules hitting both PARP and the tubulin colchicine-binding site, aiming to counter tumor heterogeneity and resistance.
- SAR work led to D13, which showed low-nanomolar antiproliferative activity across several cancer lines with good selectivity over normal cells, inhibited PARP1/2, and blocked tubulin polymerization.
- D13 caused G2/M arrest, DNA damage and apoptosis, limited migration and tube formation, and in an MDA-MB-231 xenograft outperformed veliparib, phenstatin and their combination with good tolerability.
💡 Points Based on the abstract
Dual PARP/colchicine-site agents are tough to balance: the two pharmacophores want different shapes, so I'd check that D13 isn't just a potent tubulin binder with incidental PARP activity. Key controls are PARP-null or BRCA-proficient cells, and a tubulin-inactive analog. Also, tubulin toxicity could erode the therapeutic window that PARP inhibitors normally enjoy.