STRUCTURAL EVOLUTION OF ONC201-DERIVED COMPOUNDS TARGETING THE MITOCHONDRIAL PROTEASE CLPP FOR PEDIATRIC DIFFUSE MIDLINE GLIOMA H3K27-ALTERED"

The development of ONC201-derivatives targeting the human mitochondrial protease hClpP is becoming pivotal in advancing therapeutic strategies for Diffuse Midline Glioma, including the diffuse intrinsic pontine glioma (DIPG) H3K27-altered, an extremely aggressive brain tumor primarily affecting children.1 As in other central nervous system tumors, hClpP is highly expressed at mRNA and protein levels in diffuse gliomas, potentially highlighting its possible use as a target medicine in these types of tumors.2,3 ONC201 triggers hyperactivation of hClpP, driving the proteolysis of mitochondrial proteome subunits and increasing stress response and apoptosis. Despite initial success, resistance to ONC201 has emerged in some DIPG patients, requiring the development of new compounds, such as ONC206 and ONC212, and TRs, which appear to pose significant challenges for effective treatment development.4 Efforts in medicinal chemistry have led to the synthesis of new “small molecules” and of structure-activity relationship (SAR) studies aimed to improve potency while maintaining hClpP activation (Figure 1). Among the new “small molecules”, THX6 has demonstrated efficacy in preclinical models of DIPG by selectively altering mitochondrial energy homeostasis and impairing processes essential for tumor cell survival, leading to cell death.5 This presentation will focus on the integration of medicinal chemistry approaches to prepare new hClpP activators, the knowledge of their chemical structure evolution over the years, and the elucidation of the complex hClpP-activator through broad bio-pharmaceutical characterization. The development of ONC201-derivatives targeting hClpP results in a metabolic vulnerability in DIPG cells that is hoped to lead to better therapeutic outcomes for young patients.