Nirogacestat

Nirogacestat (PF-03084014) is a selective gamma secretase inhibitor[1] developed by SpringWorks Therapeutics that has potential anti-tumor activity. It was granted FDA breakthrough drug designation in September 2019 for adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.[2]

Nirogacestat
Clinical data
Other namesPF-03084014
ATC code
  • None
Identifiers
IUPAC name
  • (S)-2-((S)-5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC27H41F2N5O
Molar mass489.656 g·mol−1
3D model (JSmol)
SMILES
  • CCC[C@@](N[C@@]1([H])CCC2=CC(F)=CC(F)=C2C1)([H])/C(O)=N/C3=CN(C(C)(CNCC(C)(C)C)C)C=N3
InChI
  • InChI=1S/C27H41F2N5O/c1-7-8-23(32-20-10-9-18-11-19(28)12-22(29)21(18)13-20)25(35)33-24-14-34(17-31-24)27(5,6)16-30-15-26(2,3)4/h11-12,14,17,20,23,30,32H,7-10,13,15-16H2,1-6H3,(H,33,35)/t20-,23-/m0/s1
  • Key:VFCRKLWBYMDAED-REWPJTCUSA-N

Medical uses

Nirogacestat is currently in Phase 2 clinical trials for unresectable desmoid tumors.[3] In addition, a Phase 3 clinical trial, DeFi, is currently in progress for nirogacestat for adults with desmoid tumors and aggressive fibromatosis.[4] In addition, three trials are presently recruiting patients that include nirogacestat with other anticancer therapies in multiple myeloma, including the UNIVERSAL study for nirogacestat with the allogeneic CAR-T therapy ALLO-715.[5][6][7]

References
  1. Chen X, Chen X, Zhou Z, Mao Y, Wang Y, Ma Z, Xu W, Qin A, Zhang S (September 2019). "Nirogacestat suppresses RANKL-Induced osteoclast formation in vitro and attenuates LPS-Induced bone resorption in vivo". Experimental Cell Research. 382 (1): 111470. doi:10.1016/j.yexcr.2019.06.015. PMID 31211955. S2CID 195065514.
  2. "FDA Grants Nirogacestat Breakthrough Designation for Desmoid Tumors". OncLive. Retrieved 2021-06-25.
  3. Clinical trial number NCT04195399 for "A Safety, Pharmacokinetic and Efficacy Study of a y-Secretase Inhibitor, Nirogacestat (PF-03084014) in Children and Adolescents With Progressive, Surgically Unresectable Desmoid Tumors" at ClinicalTrials.gov
  4. Clinical trial number NCT03785964 for "A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Nirogacestat Versus Placebo in Adult Patients With Progressing Desmoid Tumors/Aggressive Fibromatosis (DT/AF)" at ClinicalTrials.gov
  5. Clinical trial number NCT04093596 for "A Single-Arm, Open-Label, Phase 1 Study of the Safety, Efficacy, and Cellular Kinetics/Pharmacodynamics of ALLO-715 to Evaluate an Anti-BCMA Allogeneic CAR T Cell Therapy With or Without Nirogacestat in Subjects With Relapsed/Refractory Multiple Myeloma" at ClinicalTrials.gov
  6. Clinical trial number NCT04722146 for "A Multi-arm Phase 1b Study of Teclistamab With Other Anticancer Therapies in Participants With Multiple Myeloma" at ClinicalTrials.gov
  7. Clinical trial number NCT04126200 for "A Phase I/II, Randomized, Open-label Platform Study Utilizing a Master Protocol to Study Belantamab Mafodotin (GSK2857916) as Monotherapy and in Combination With Anti-Cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) - DREAMM 5" at ClinicalTrials.gov


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