Diffuse midline glioma (DMG) is a fatal childhood CNS tumor whose treatment is still a challenge. DMG is has extremely poor prognosis due to localization and inoperability. Current treatments are limited to irradiation which only prolongs survival by a few months. Preclinical studies identified drug candidates, but their translation into the clinic remains a major obstacle. Over the past decade, ONC201, a known dopamine receptor antagonist, was discovered from a high-throughput screening of public libraries of compounds, to be endowed with cytotoxic activity against several tumor cell lines including glioma. Efforts to discover the true ONC201 target allow to identify Homo sapiens P caseinolytic mitochondrial protease (HsClpP) as responsible for its antiproliferative effect. Enhancement of HsClpP activity leads to its dysregulation useful in cancer therapeutics. HsClpP is overexpressed in multiple tumor cell types, such as DMG, to be considered a promising therapeutic target for its treatment. ONC201 reached DMG Phase III clinical trial. ONC201 and HsClpP co-crystal provided information on the aminoacids involved in the binding and structural features of HsClpP inducers. The identification of new therapeutic indications for marketed drugs represents one of the strategies (repurposing) to find treatments more quickly for diseases still lacking medications. Active principle ingredients (APIs) of natural origin present in known drugs can be used as they are (repurposing) or structurally ‘optimized’ by evolution to serve biological functions, including the regulation of endogenous defense mechanisms and the interaction with other organisms, which explains their high relevance for infectious diseases and cancer. APIs are characterized by enormous scaffold diversity and structural complexity. Thus, a Structure Based Virtual Screening of natural products (NPs), based on the Fingerprints for Ligands and Proteins (FLAP) algorithm, has been carrying out to identify a novel original scaffold as HsClpP inducers. The result of this screening, as well of the biological evaluation as protease inducers will be presented. [1] Perrone M.G. et al. Diffuse Intrinsic Pontine Glioma (DIPG): Breakthrough and Clinical Perspective Curr. Med.Chem. 2020, 27, 1-30.
Repurposing of natural origin compounds as HsClpP inducers to treat diffuse midline glioma (DMG)
Perrone M. G.;Miciaccia M.;Solidoro R.;Ferorelli S.;Scilimati A
2022-01-01
Abstract
Diffuse midline glioma (DMG) is a fatal childhood CNS tumor whose treatment is still a challenge. DMG is has extremely poor prognosis due to localization and inoperability. Current treatments are limited to irradiation which only prolongs survival by a few months. Preclinical studies identified drug candidates, but their translation into the clinic remains a major obstacle. Over the past decade, ONC201, a known dopamine receptor antagonist, was discovered from a high-throughput screening of public libraries of compounds, to be endowed with cytotoxic activity against several tumor cell lines including glioma. Efforts to discover the true ONC201 target allow to identify Homo sapiens P caseinolytic mitochondrial protease (HsClpP) as responsible for its antiproliferative effect. Enhancement of HsClpP activity leads to its dysregulation useful in cancer therapeutics. HsClpP is overexpressed in multiple tumor cell types, such as DMG, to be considered a promising therapeutic target for its treatment. ONC201 reached DMG Phase III clinical trial. ONC201 and HsClpP co-crystal provided information on the aminoacids involved in the binding and structural features of HsClpP inducers. The identification of new therapeutic indications for marketed drugs represents one of the strategies (repurposing) to find treatments more quickly for diseases still lacking medications. Active principle ingredients (APIs) of natural origin present in known drugs can be used as they are (repurposing) or structurally ‘optimized’ by evolution to serve biological functions, including the regulation of endogenous defense mechanisms and the interaction with other organisms, which explains their high relevance for infectious diseases and cancer. APIs are characterized by enormous scaffold diversity and structural complexity. Thus, a Structure Based Virtual Screening of natural products (NPs), based on the Fingerprints for Ligands and Proteins (FLAP) algorithm, has been carrying out to identify a novel original scaffold as HsClpP inducers. The result of this screening, as well of the biological evaluation as protease inducers will be presented. [1] Perrone M.G. et al. Diffuse Intrinsic Pontine Glioma (DIPG): Breakthrough and Clinical Perspective Curr. Med.Chem. 2020, 27, 1-30.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
