Human Caseinolytic peptidase P (hClpP) is a key inducer of mitochondrial protein quality control for the clearance of misfolded or damaged proteins which are necessary for maintaining mitochondrial functions. Alterated activities of this protease are correlated with tumor development and progression. HClpP modulates cancer cell viability, reactive oxygen species (ROS) levels, and metabolic reprogramming under hypoxia, oxidative stress, or starvation. Consequently, inhibition or hyperactivation of this protease may be a potential therapeutic strategy for cancer treatment. The involvement of hClpP in cancer, is corroborated by the results obtained by its activator, named ONC201, an imipridone, that disrupts the ClpXP complex, by physically displacing ClpX from ClpP while keeping hClpP in its activated state. ONC201 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, and the Food and Drug Administration granted Fast Track designation to ONC201 for the treatment of highgrade glioma with recurrent H3-K27M mutation in adults. Diffuse Intrinsic Pontine Glioma (DIPG) is a subgroup of DMG, an astrocytoma involving the pons, a region of the brain stem, consisting in a broad horseshoeshaped mass of transverse nerve fibres that connect the medulla with the cerebellum. The pons, while involved in the regulation of functions carried out by the cranial nerves it houses, works together with the medulla oblongata to serve an especially critical role in generating the respiratory rhythm of breathing. Active functioning of the pons may also be fundamental to rapid eye movement (REM) sleep. The sensitivity of the affected region of the pons makes DIPG unsuitable for surgical resection and its current standard care is limited to focal radiotherapy providing only a limited and temporary benefit for patient survival. In the last decade, advances in genomic knowledge have made it possible to establish that in most cases (80%) of DIPG there is a K27M mutation of histone H3: hence the definition of "Diffuse gliomas of the midline H3K27M mutated”. ONC201 and hClpP co-crystal provided information on the amino acids involved in the binding and structural features of its activators. 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 hClpP inducers. The result of this screening, as well of the biological evaluation as protease inducers will be presented.
Human Caseinolytic Protease P (hClpP) Activity Modulating Agents For The Treatment Of DIPG/DMG
Perrone M. G.;Miciaccia M.;Baldelli O.;Ferorelli S.;Scilimati A.
2023-01-01
Abstract
Human Caseinolytic peptidase P (hClpP) is a key inducer of mitochondrial protein quality control for the clearance of misfolded or damaged proteins which are necessary for maintaining mitochondrial functions. Alterated activities of this protease are correlated with tumor development and progression. HClpP modulates cancer cell viability, reactive oxygen species (ROS) levels, and metabolic reprogramming under hypoxia, oxidative stress, or starvation. Consequently, inhibition or hyperactivation of this protease may be a potential therapeutic strategy for cancer treatment. The involvement of hClpP in cancer, is corroborated by the results obtained by its activator, named ONC201, an imipridone, that disrupts the ClpXP complex, by physically displacing ClpX from ClpP while keeping hClpP in its activated state. ONC201 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, and the Food and Drug Administration granted Fast Track designation to ONC201 for the treatment of highgrade glioma with recurrent H3-K27M mutation in adults. Diffuse Intrinsic Pontine Glioma (DIPG) is a subgroup of DMG, an astrocytoma involving the pons, a region of the brain stem, consisting in a broad horseshoeshaped mass of transverse nerve fibres that connect the medulla with the cerebellum. The pons, while involved in the regulation of functions carried out by the cranial nerves it houses, works together with the medulla oblongata to serve an especially critical role in generating the respiratory rhythm of breathing. Active functioning of the pons may also be fundamental to rapid eye movement (REM) sleep. The sensitivity of the affected region of the pons makes DIPG unsuitable for surgical resection and its current standard care is limited to focal radiotherapy providing only a limited and temporary benefit for patient survival. In the last decade, advances in genomic knowledge have made it possible to establish that in most cases (80%) of DIPG there is a K27M mutation of histone H3: hence the definition of "Diffuse gliomas of the midline H3K27M mutated”. ONC201 and hClpP co-crystal provided information on the amino acids involved in the binding and structural features of its activators. 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 hClpP inducers. The result of this screening, as well of the biological evaluation as protease inducers will be presented.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
