ONC201/dordaviprone for H3 K27M-mutant tumors: Discovery, mechanisms, therapeutic potential, and future directions.

ONC201 (dordaviprone) has recently received accelerated approval for the treatment of recurrent H3 K27M-mutant diffuse midline glioma. Originally identified as TRAIL-inducing compound 10 (TIC10), ONC201 is a first-in-class small molecule distinguished by a unique pharmacologic profile. It promotes apoptosis through multiple convergent mechanisms, including upregulation of TRAIL, activation of the integrated stress response (ISR), direct allosteric activation of the mitochondrial protease ClpP, and antagonism of dopamine receptor D2 (DRD2). These pathways converge to engage both extrinsic and intrinsic apoptotic programs, disrupt mitochondrial bioenergetics, and reprogram survival signaling, distinguishing ONC201 from conventional cytotoxic and targeted agents. Preclinical studies have demonstrated broad antitumor efficacy across diverse cancer models. Clinically, ONC201 has progressed rapidly through early-phase trials, establishing a favorable safety and pharmacokinetic profile, with sustained biological activity and weekly oral dosing. Pivotal trials in H3 K27M-mutant diffuse midline glioma demonstrated meaningful clinical benefit, leading to accelerated regulatory approval and making it the first therapy to receive such approval for this devastating disease. Ongoing studies are expanding ONC201's clinical applications to hematologic malignancies and gynecologic cancers, as well as to combination regimens. Despite these advances, emerging resistance mechanisms, including ClpP mutations and adaptive activation of the EGFR and MAPK/AKT pathways, highlight the need for biomarker development and rational combination strategies. Together, these insights position ONC201 as both a therapeutic milestone and a platform for future translational oncology innovation.