Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor which accounts for about 10% to 20% of all childhood brain tumors1, with a peak of incidence between 6 and 8 years. Prognosis is extremely poor, due to localization and inoperability. Indeed, surgery cannot be performed, and focal radiotherapy remains the standard of care currently that has demonstrated clinical efficacy. Over the last decade, preclinical studies identified ONC201, an experimental anticancer drug from the imipridone class to be endowed with cytotoxic activity against multiple human cancer cell lines, including DIPG. Only recently, the X-ray analysis of the complex of the human mitochondrial caseinolytic serine protease type C (hClpP) and ONC201 (PDB ID: 6DL7, Figure 1)2, has allowed to identify hClpP as its main direct target. This provided the rationale to evaluate the hClpP activity in patients recruited in ongoing clinical trials using ONC201 as a drug. Downstream of target engagement, hClpP plays a pivotal role in the quality control of mitochondrial proteins involved in important cellular pathways. The hyperactivation of hClpP, due to the interaction with ONC201, alters the structure and mitochondrial function, causes the death of cancer cells, without affecting healthy cells. To date, a computational pipeline was applied to perform a FLAP virtual screening of 1500 commercial natural products (CNPs) followed by Volsurf analysis to identify a novel original scaffold as hClpP inducers able to cross blood-barrier brain. In silico investigation identifies Harmaline, a fluorescent indole alkaloid, with anti-inflammatory and anti-cancer properties. Harmaline chemical structure has been pportunely modified to find out structural determinants for the hClpP induction. The Structure Activity Relationship Study results will be presented and discussed.
Harmaline-based scaffold as Human Caseinolytic Protease P (hClpP) inducers for Diffuse Intrinsic Pontine Glioma (DIPG) treatment
Morena MiciacciaMembro del Collaboration Group
;Olga BaldelliMembro del Collaboration Group
;Roberta SolidoroMembro del Collaboration Group
;Savina FerorelliMembro del Collaboration Group
;Maria Grazia PerroneMembro del Collaboration Group
;Antonio ScilimatiMembro del Collaboration Group
2023-01-01
Abstract
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor which accounts for about 10% to 20% of all childhood brain tumors1, with a peak of incidence between 6 and 8 years. Prognosis is extremely poor, due to localization and inoperability. Indeed, surgery cannot be performed, and focal radiotherapy remains the standard of care currently that has demonstrated clinical efficacy. Over the last decade, preclinical studies identified ONC201, an experimental anticancer drug from the imipridone class to be endowed with cytotoxic activity against multiple human cancer cell lines, including DIPG. Only recently, the X-ray analysis of the complex of the human mitochondrial caseinolytic serine protease type C (hClpP) and ONC201 (PDB ID: 6DL7, Figure 1)2, has allowed to identify hClpP as its main direct target. This provided the rationale to evaluate the hClpP activity in patients recruited in ongoing clinical trials using ONC201 as a drug. Downstream of target engagement, hClpP plays a pivotal role in the quality control of mitochondrial proteins involved in important cellular pathways. The hyperactivation of hClpP, due to the interaction with ONC201, alters the structure and mitochondrial function, causes the death of cancer cells, without affecting healthy cells. To date, a computational pipeline was applied to perform a FLAP virtual screening of 1500 commercial natural products (CNPs) followed by Volsurf analysis to identify a novel original scaffold as hClpP inducers able to cross blood-barrier brain. In silico investigation identifies Harmaline, a fluorescent indole alkaloid, with anti-inflammatory and anti-cancer properties. Harmaline chemical structure has been pportunely modified to find out structural determinants for the hClpP induction. The Structure Activity Relationship Study results will be presented and discussed.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
