targetsTarget

Gamma-secretase (PSEN1)

The membrane enzyme that releases the active part of Notch. Nirogacestat blocks it and became the first drug approved for desmoid tumours, the aggressive but non-metastasising growths driven by Wnt signalling.

Gamma-secretase is a four-protein complex whose catalytic core, presenilin 1, cleaves membrane proteins including Notch receptors and amyloid precursor protein. Cleaving Notch releases its intracellular domain, so blocking gamma-secretase shuts down Notch signalling, which desmoid tumours depend on alongside their Wnt pathway mutations. Nirogacestat, approved in 2023 after the DeFi trial, shrinks desmoid tumours and reduces pain, at the cost of diarrhoea and ovarian toxicity in women. Earlier gamma-secretase inhibitors failed in Alzheimer disease and in T-cell leukaemia because of gut toxicity, and the same class is now used to unmask BCMA on myeloma cells to improve BCMA-directed therapy.

Gamma-secretase (PSEN1): what it is and how drugs act on it · animated generic schematic, not to scale

Target · the protein and the cell it sits on
Drug · antibody, small molecule, cell or radioligand
Effect · signal, damage or kill

In plain words · The membrane enzyme that releases the active part of Notch. Nirogacestat blocks it and became the first drug approved for desmoid tumours, the aggressive but non-metastasising growths driven by Wnt signalling.

1 · What it is
The membrane enzyme that releases the active part of Notch. Nirogacestat blocks it and became the first drug approved for desmoid tumours, the aggressive but non-metastasising growths driven by Wnt signalling.
2 · What goes wrong in cancer
Intramembrane aspartyl protease complex (PSEN1 or PSEN2, nicastrin, APH1, PEN2) that releases the Notch intracellular domain.
3 · How drugs use it
No product in this corpus aims at Gamma-secretase (PSEN1) yet. Inhibitors are shaped to fit the enzyme's active site so the reaction the cancer relies on stops.