# Gamma-secretase inhibitors

Source: https://onco.cc/technologies/gamma-secretase-inhibitors/  
OnCo record `gamma-secretase-inhibitors` (Technology). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Drugs that block the enzyme that activates Notch signalling; nirogacestat became the first approved, in 2023, for desmoid tumours, a rare but destructive growth of connective tissue.

## Summary

Gamma-secretase cleaves Notch receptors to release their active fragment. Inhibitors developed originally for Alzheimer's disease were repurposed for Notch-driven cancers; nirogacestat (Ogsiveo) reduced progression and pain in desmoid tumours in the DeFi trial and was approved by the FDA in 2023. Gamma-secretase inhibition also boosts BCMA on myeloma cells, so it is combined with BCMA-directed CAR-T and bispecifics, and T-cell acute lymphoblastic leukaemia remains a target despite gut toxicity.

## Fields

- Kind: Technology
- Status: approved
- Last checked: 2026-09-04
- Principle: Small molecules inhibit the presenilin catalytic site of gamma-secretase, preventing Notch intracellular domain release and Notch target gene transcription.
- Since: 2023
- Strengths: First approved therapy for desmoid tumours; Increases BCMA density for myeloma immunotherapies
- Limitations: Diarrhoea and ovarian toxicity; Notch inhibition affects normal gut and immune cells

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Gamma_secretase
- Wikipedia: https://en.wikipedia.org/wiki/Gamma_secretase

## Connected records

- cancers: [Multiple myeloma](https://onco.cc/cancers/multiple-myeloma/), [Sarcomas (soft tissue, bone, GIST)](https://onco.cc/cancers/sarcoma/)
- fronts: [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- targets: [Gamma-secretase (PSEN1)](https://onco.cc/targets/gamma-secretase/)
- drugs: [Nirogacestat](https://onco.cc/drugs/nirogacestat/)
- trials: [A Study of Nirogacestat in Japanese Adults With Desmoid Tumors/Aggressive Fibromatosis (DT/AF)](https://onco.cc/trials/nct07170644/), [DeFi](https://onco.cc/trials/defi/), [Sub-study of Belantamab Mafodotin (GSK2857916) as Monotherapy and in Combination With Nirogacestat, Pomalidomide, and Dexamethasone in Participants Wi](https://onco.cc/trials/nct07150104/), [Sub-study of Belantamab Mafodotin (GSK2857916) in Combination With Nirogacestat in Participants With RRMM](https://onco.cc/trials/nct07084896/), [Sub-study of Belantamab Mafodotin (GSK2857916) in Combination With Nirogacestat, Lenalidomide, and Dexamethasone in Participants With RRMM](https://onco.cc/trials/nct07150091/)
- technologies: [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)

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