Gamma-secretase inhibitors
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.
Overview
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.
How it works
Small molecules inhibit the presenilin catalytic site of gamma-secretase, preventing Notch intracellular domain release and Notch target gene transcription.
- First approved therapy for desmoid tumours
- Increases BCMA density for myeloma immunotherapies
- Diarrhoea and ovarian toxicity
- Notch inhibition affects normal gut and immune cells
Latest papers
topQuery for this technology: (TITLE:"Gamma-secretase inhibitors" OR ABSTRACT:"Gamma-secretase inhibitors") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about Gamma-secretase inhibitors, not a curated reading list.
Similar pages
not linked directly; found by shared links- TrialDeFi
- CompanySpringWorks Therapeutics (Merck KGaA)
- IdeaIntermittent or stop-and-restart nirogacestat in desmoid tumours
- TreatmentPegylated liposomal doxorubicin
Shares Sarcomas (soft tissue, bone, GIST), Multiple myeloma.
- CancerDesmoid tumour
Shares Gamma-secretase (PSEN1), Nirogacestat, Sarcomas (soft tissue, bone, GIST).
- IdeaMilestone-based venture philanthropy with royalties recycled into the pipeline
Shares Sarcomas (soft tissue, bone, GIST), Multiple myeloma.