Semagacestat

Summary

Semagacestat (CHEMBL520733) is a phase-3 clinical-stage small molecule targeting PSEN1; indicated across 1 condition including alzheimer disease.

At a glance

• Status: Max clinical phase 3 (not approved)
• Modality: Small molecule
• Targets: 1 (PSEN1)
• Indications: 1 condition
• Clinical trials: 5
• Chemistry: 361.4 Da · C19H27N3O4

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL520733
Name	Semagacestat
Type	Small molecule
Max phase	3
FDA approved	no
PubChem CID	9843750
Molecular formula	C19H27N3O4
Molecular weight	361.4
InChIKey	PKXWXXPNHIWQHW-RCBQFDQVSA-N

SMILES: C[C@@H](C(=O)N[C@H]1C2=CC=CC=C2CCN(C1=O)C)NC(=O)[C@H](C(C)C)O

IUPAC name: (2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihydro-1H-3-benzazepin-5-yl]amino]-1-oxopropan-2-yl]butanamide

Also known as: LY-450139, LY450139, Semagacestat, semagacestat, SEMAGACESTAT, Semagasestat, Semagacestat (LY450139)

Patent coverage: 304 distinct patent families (701 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 517 (74%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
PSEN1	presenilin 1	Inhibition	7.82	0.8%	P49768

Broader ChEMBL bioactivity targets: 1 (assay-derived). Sample: Gamma-secretase.

Bioactivity

ChEMBL activities: 13 potent at pChembl ≥ 5 of 13 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
PSEN1	8.49	IC50	3.2	nM	CHEMBL_ACT_13359317
PSEN1	8.1	IC50	7.9	nM	CHEMBL_ACT_13359334
PSEN1	7.96	IC50	10.9	nM	CHEMBL_ACT_19427651
PSEN1	7.96	IC50	10.9	nM	CHEMBL_ACT_24776264
PSEN1	7.85	IC50	14.1	nM	CHEMBL_ACT_19427650
PSEN1	7.42	IC50	38	nM	CHEMBL_ACT_3255083
PSEN1	7.42	IC50	38	nM	CHEMBL_ACT_3255090
PSEN1	7.4	IC50	39.81	nM	CHEMBL_ACT_3105162
PSEN1	7.4	IC50	39.81	nM	CHEMBL_ACT_3105188
PSEN1	7	IC50	100	nM	CHEMBL_ACT_3105306
PSEN1	6.9	IC50	125.9	nM	CHEMBL_ACT_3105282
PSEN1	6.9	EC50	125.9	nM	CHEMBL_ACT_3105290
PSEN1	6.7	IC50	199.5	nM	CHEMBL_ACT_3105298

Target pathways

Aggregated over 1 target gene(s): PSEN1.

Top Reactome pathways

14 total, by targets touching each:

Pathway	Targets	Genes
Nuclear signaling by ERBB4	1	PSEN1
Degradation of the extracellular matrix	1	PSEN1
Regulated proteolysis of p75NTR	1	PSEN1
NRIF signals cell death from the nucleus	1	PSEN1
Activated NOTCH1 Transmits Signal to the Nucleus	1	PSEN1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	PSEN1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	PSEN1
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	PSEN1
EPH-ephrin mediated repulsion of cells	1	PSEN1
Neutrophil degranulation	1	PSEN1
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	PSEN1
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	PSEN1
Noncanonical activation of NOTCH3	1	PSEN1
TGFBR3 PTM regulation	1	PSEN1

Dominant GO biological processes

GO term	Targets
autophagosome assembly	1
negative regulation of transcription by RNA polymerase II	1
blood vessel development	1
cell fate specification	1
somitogenesis	1
neuron migration	1
positive regulation of receptor recycling	1
heart looping	1
positive regulation of L-glutamate import across plasma membrane	1
hematopoietic progenitor cell differentiation	1
astrocyte activation involved in immune response	1
T cell activation involved in immune response	1
neural retina development	1
membrane protein ectodomain proteolysis	1
mitochondrial transport	1

Indications & clinical

Indications

1 indication (0 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
Alzheimer disease	3	MONDO:0004975	MONDO:0004975

Clinical trials

Total trials: 5.

Phase distribution

Phase	Trials
PHASE3	3
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00594568	PHASE3	COMPLETED	Effect of LY450139 on the Long Term Progression of Alzheimer’s Disease
NCT00762411	PHASE3	COMPLETED	Effects of LY450139, on the Progression of Alzheimer’s Disease as Compared With Placebo
NCT01035138	PHASE3	COMPLETED	A Study of Semagacestat for Alzheimer’s Patients
NCT00244322	PHASE2	COMPLETED	Effects of LY450139 Dihydrate on Subjects With Mild to Moderate Alzheimer’s Disease
NCT00765115	PHASE1	COMPLETED	A Study of Healthy Subjects to Assess the Effect of LY450139 on Amyloid Beta Peptide Production Rate and or Dose Response.

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

Pharmacology

Pharmacogenomics

No PharmGKB pharmacogenomic data curated for this drug.

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

5 molecules share ≥1 primary target. Top 5 by shared-target count:

Molecule	Source	Status	Shared targets
NIROGACESTAT	ChEMBL	Phase 4 (approved)	PSEN1
TARENFLURBIL	ChEMBL	Phase 3	PSEN1
AVAGACESTAT	ChEMBL	Phase 2	PSEN1
BEGACESTAT	ChEMBL	Phase 2	PSEN1
RG-4733	ChEMBL	Phase 2	PSEN1