{"entity":{"id":"gamma-secretase-inhibitors","kind":"technology","name":"Gamma-secretase inhibitors","aka":[],"tldr":"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.","status":"approved","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Gamma_secretase","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Gamma_secretase"}],"tags":[],"related":[],"cancers":["sarcoma","multiple-myeloma"],"sections":["targeted-therapy"],"technologies":[],"targets":["gamma-secretase"],"drugs":["nirogacestat"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"principle":"Small molecules inhibit the presenilin catalytic site of gamma-secretase, preventing Notch intracellular domain release and Notch target gene transcription.","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"],"since":2023},"route":"/technologies/gamma-secretase-inhibitors/","neighbours":{"cancer":[{"id":"multiple-myeloma","kind":"cancer","name":"Multiple myeloma","route":"/cancers/multiple-myeloma/"},{"id":"sarcoma","kind":"cancer","name":"Sarcomas (soft tissue, bone, GIST)","route":"/cancers/sarcoma/"}],"section":[{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"target":[{"id":"gamma-secretase","kind":"target","name":"Gamma-secretase (PSEN1)","route":"/targets/gamma-secretase/"}],"drug":[{"id":"nirogacestat","kind":"drug","name":"Nirogacestat","route":"/drugs/nirogacestat/"}],"trial":[{"id":"nct07170644","kind":"trial","name":"A Study of Nirogacestat in Japanese Adults With Desmoid Tumors/Aggressive Fibromatosis (DT/AF)","route":"/trials/nct07170644/"},{"id":"defi","kind":"trial","name":"DeFi","route":"/trials/defi/"},{"id":"nct07150104","kind":"trial","name":"Sub-study of Belantamab Mafodotin (GSK2857916) as Monotherapy and in Combination With Nirogacestat, Pomalidomide, and Dexamethasone in Participants Wi","route":"/trials/nct07150104/"},{"id":"nct07084896","kind":"trial","name":"Sub-study of Belantamab Mafodotin (GSK2857916) in Combination With Nirogacestat in Participants With RRMM","route":"/trials/nct07084896/"},{"id":"nct07150091","kind":"trial","name":"Sub-study of Belantamab Mafodotin (GSK2857916) in Combination With Nirogacestat, Lenalidomide, and Dexamethasone in Participants With RRMM","route":"/trials/nct07150091/"}],"technology":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]}}