Dual treatment with Val-083 and AZD1775 shows potent anti-tumor activity in diffuse midline glioma models.

ABSTRACT: H3K27M diffuse midline gliomas (DMG) are characterized by p53 mutations and hypomethylation of MGMT, a DNA-repair enzyme, leading to resistance towards chemotherapeutic agents such as temozolomide (TMZ). As an alternative, we investigated the efficacy of a functionally different DNA-damaging agent, Val-083, on our DMG models. Val-083 is a blood-brain barrier penetrant DNA targeting agent that induces DNA N7-guanine interstrand crosslinks, which is unrepairable by MGMT. As Val-083 also triggers S/G2 phase cell cycle arrest for DNA repair, we evaluated its combined efficacy with Wee1 inhibitor, AZD1775. AZD1775 functions by inhibiting Wee1, at G2/M checkpoint to prevent phosphorylation of CDK1 and propel cells into the M phase. This subsequently overrides cell cycle arrest and drives cells w

SUBMITTER: Subramaniam B 

PROVIDER: S-EPMC12215462 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature