KU-0060648

KU-0060648 is a potent, dual small molecule inhibitor of **DNA-dependent protein kinase (DNA-PK)** and **phosphoinositide 3-kinases (PI3Ks)**, showing highest potency against the PI3Kδ isoform and substantial activity against DNA-PK and other class I PI3K isoforms (PI3Kα, PI3Kβ)[1][3][5][8]. It selectively blocks the repair of DNA double-strand breaks by inhibiting DNA-PK, interfering with non-homologous end joining (NHEJ) repair, and suppresses the PI3K/AKT pathway involved in cellular growth and survival[1][3][5][8]. The compound was designed as an anti-cancer agent; it inhibits proliferation in multiple cancer cell lines (notably MCF7 breast cancer and LoVo colon cancer), both as a single agent and as a chemosensitizer in combination with topoisomerase II poisons such as etoposide and doxorubicin[1][3][5]. It demonstrates cell-line- and context-dependent anti-tumor activity and enhances the efficacy of DNA-damaging chemotherapies[1]. KU-0060648 has also been used to improve CRISPR/Cas9-mediated homology-directed repair by inhibiting NHEJ and favoring homologous recombination[3].