Brain-penetrant small molecule agents possessing a dual targeting mechanism of action (LonP1 and CT-L proteasome inhibition) that may overcome resistance mechanisms that currently plague standard of care treatments for brain tumors such as glioblastoma.
Background:
Malignant astrocytomas, including glioblastoma (GBM), represent highly aggressive intracranial tumors with notoriously poor clinical outcomes due to the profound limitations of current standard-of-care therapies. GBM is characterized by near-universal recurrence following first-line treatment and, critically, no approved therapy currently exists to meaningfully extend survival once recurrence occurs. Existing treatments are limited and often fail due to the rapid emergence of resistance and the formidable obstacle of the blood-brain barrier, which severely restricts the penetration and accumulation of systemically administered drugs at the tumor site. Furthermore, these tumors exhibit remarkable adaptability, often hijacking intrinsic cellular survival mechanisms—such as mitochondrial stress responses and proteasomal protein degradation pathways—to mitigate proteotoxic stress and evade cell death. Consequently, the inability of conventional therapies to achieve adequate brain exposure while simultaneously overcoming these deeply entrenched, stress-adaptive resistance pathways remains a critical barrier to achieving durable tumor control in patients with malignant gliomas.
Technology Overview:
Researchers at the University at Buffalo have developed a series of brain-penetrant small molecules that dually target mitochondrial Lon peptidase 1 (LonP1) and chymotrypsin-like proteasome activity to treat malignant brain tumors such as GBM. Lon is overexpressed in human malignant gliomas and its elevated expression levels are associated with high glioma tumor grade and poor patient survival. Therefore, regulation of mitochondrial function by inhibiting Lon protease could represent a novel approach for GBM and potentially other fast-growing malignancies which heavily depend on hypoxic adaptation. Compared to existing treatments, which typically rely on DNA damage or anti-angiogenesis and frequently fail due to reasons relating to resistance and/or poor penetration, this novel approach, wherein these agents simultaneously drive lethal proteotoxic stress and mitochondrial dysfunction within tumor cells, may overcome key resistance mechanisms while achieving effective intracranial exposure for practical, outpatient tumor control.
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Source: SciePro, https://stock.adobe.com/uk/22202817, stock.adobe.com
Advantages:
Applications:
Intellectual Property Summary:
Patent pending.
Stage of Development:
In vitro
Licensing Status:
Available for licensing or collaboration.
Publication link(s):
No publications to date.