One of the major pathways of double-strand breaks (DSB) repair is non-homologous end joining (NHEJ). DNA-dependent protein kinase (DNA‑PK) is thought to be induced by exposure to cancer therapeutics. DNA‑PK is integral to DSB repair; this contributes to the survival of cancer cells exposed to double-stranded break-inducing therapies.1-3
Replication stress results in DSBs in DNA which is recognized by DNA‑PKcs. DNA‑PKcs subsequently binds to Ku to form the DNA‑PK complex. Other factors are recruited to form the NHEJ complex at the double-strand break. DNA‑PK phosphorylation induces a conformational change in NHEJ, which enables DNA repair.2-4
Peposertib (DNA‑PK inhibitor)
Description and Potential Mechanism of Action:
Pepostertib (formerly M3814) is an investigational molecule inhibitor of DNA‑PK. DNA‑PK is an enzyme for NHEJ, an important DNA DSB repair pathway. DNA‑PK inhibition impairs NHEJ repair, leading to persistent DNA double-strand breaks and subsequent tumor cell death.5,6
Peposertib is an investigational orally administered, molecule, selective DNA‑PK inhibitor designed to block DNA‑PK activity. This inhibits its ability to function in the DNA repair process leading to the persistence of DNA DSBs and subsequent cell death.5
