Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT9W8GU)

• DTT Name: Gamma-secretase (GS)
• Synonyms: Presenilin-stabilization factor-like; PSFL; Aph-1beta
• Gene Name: APH1A
• DTT Type: Clinical trial target; [1]
• UniProt ID: APH1A_HUMAN ; APH1B_HUMAN ; PEN2_HUMAN ; NICA_HUMAN ; PSN1_HUMAN
• TTD ID: T99840
• Sequence:
  MGAAVFFGCTFVAFGPAFALFLITVAGDPLRVIILVAGAFFWLVSLLLASVVWFILVHVT
  DRSDARLQYGLLIFGAAVSVLLQEVFRFAYYKLLKKADEGLASLSEDGRSPISIRQMAYV
  SGLSFGIISGVFSVINILADALGPGVVGIHGDSPYYFLTSAFLTAAIILLHTFWGVVFFD
  ACERRRYWALGLVVGSHLLTSGLTFLNPWYEASLLPIYAVTVSMGLWAFITAGGSLRSIQ
  RSLLCRRQEDSRVMVYSALRIPPED
• Function: Probable subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral proteins such as Notch receptors and APP (beta-amyloid precursor protein). It probably represents a stabilizing cofactor for the presenilin homodimer that promotes the formation of a stable complex. Probably present in a minority of gamma-secretase complexes compared to APH1A.
• KEGG Pathway:
  Notch signaling pathway (hsa04330)
  Alzheimer's disease (hsa05010)
• Reactome Pathway:
  Regulated proteolysis of p75NTR (R-HSA-193692)
  NRIF signals cell death from the nucleus (R-HSA-205043)
  Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  NOTCH2 Activation and Transmission of Signal to the Nucleus (R-HSA-2979096)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  Nuclear signaling by ERBB4 (R-HSA-1251985)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Nirogacestat	DMUP5Z0	Desmoid tumour	2F7C	Approved	[2]

16 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(S)-FLURBIPROFEN	DMF2O4T	Myalgia	FB56.2	Preregistration	[3]
AMG 386	DMQJXL4	Breast cancer	2C60-2C65	Phase 3	[4]
Semagacestat	DML83IW	Parkinson disease	8A00.0	Phase 3	[1]
AL102	DMCTWIB	Desmoid tumour	2F7C	Phase 2	[5]
BMS-708163	DM51LTG	Alzheimer disease	8A20	Phase 2	[6]
CHF-5074	DMTE071	Alzheimer disease	8A20	Phase 2	[7]
MK-0752	DMLTAES	Alzheimer disease	8A20	Phase 2	[8]
R-flurbiprofen	DMFIVSR	N. A.	N. A.	Phase 2	[3]
RO-4929097	DMXA6B3	Breast cancer	2C60-2C65	Phase 2	[9]
Begacestat	DMUR49N	Alzheimer disease	8A20	Phase 1	[10]
E-2212	DMQDKYV	Alzheimer disease	8A20	Phase 1	[11]
E2012	DMNEVKA	Alzheimer disease	8A20	Phase 1	[12]
GSI-136	DMSR5HD	Alzheimer disease	8A20	Phase 1	[13]
NGP 555	DMTVQH2	Alzheimer disease	8A20	Phase 1	[14]
PF-06648671	DM056JD	Alzheimer disease	8A20	Phase 1	[14]
SPI-014	DM5IPUS	Alzheimer disease	8A20	Phase 1	[15]

8 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(2S,3R)-2-(benzyloxy)-3-methoxycyclohexanone	DMJE83O	Discovery agent	N.A.	Investigative	[16]
(5R,6S)-5,6-bis(benzyloxy)cyclohex-2-enone	DMREVX9	Discovery agent	N.A.	Investigative	[16]
(5R,6S)-6-(benzyloxy)-5-methoxycyclohex-2-enone	DMHG7MU	Discovery agent	N.A.	Investigative	[16]
1-benzoyl-2-benzyl-1,2-dihydropyridin-3(6H)-one	DMF9X2T	Discovery agent	N.A.	Investigative	[16]
Drug 311383	DM5QUJV	Discovery agent	N.A.	Investigative	[17]
Drug 311440	DMOIFBK	Discovery agent	N.A.	Investigative	[17]
Drug 311951	DMXTCJ1	Discovery agent	N.A.	Investigative	[17]
Drug 311952	DM27ILS	Discovery agent	N.A.	Investigative	[17]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Breast cancer	2C82	Breast tissue	1.90E-10	0.81	0.65
Alzheimer's disease	8A00.0	Entorhinal cortex	1.47E-02	-0.09	-0.37
Parkinson's disease	8A00.0	Substantia nigra tissue	4.02E-01	-0.27	-0.71

References

• [1] A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013 Jul 25;369(4):341-50.
• [2] Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014.J Pharmacol Exp Ther.2010 Jul;334(1):269-77.
• [3] The geminal dimethyl analogue of Flurbiprofen as a novel Abeta42 inhibitor and potential Alzheimer's disease modifying agent. Bioorg Med Chem Lett. 2006 Apr 15;16(8):2219-23.
• [4] Clinical pipeline report, company report or official report of Roche (2009).
• [5] Clinical pipeline report, company report or official report of Ayala Pharmaceuticals.
• [6] Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012 Nov;69(11):1430-40.
• [7] CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease.Br J Pharmacol.2009 Mar;156(6):982-93.
• [8] Determination of the gamma-secretase inhibitor MK-0752 in human plasma by online extraction and electrospray tandem mass spectrometry (HTLC-ESI-MS/MS). J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Sep 1;878(25):2348-52.
• [9] Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. J Clin Oncol. 2012 Jul 1;30(19):2348-53.
• [10] Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease. J Pharmacol Exp Ther. 2009 Nov;331(2):598-608.
• [11] Development and mechanism of gamma-secretase modulators for Alzheimer's disease. Biochemistry. 2013 May 14;52(19):3197-216.
• [12] Chemical Biology, Molecular Mechanism and Clinical Perspective of -Secretase Modulators in Alzheimer's Disease.Curr Neuropharmacol.2011 Dec;9(4):598-622.
• [13] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [14] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [15] Modulation of gamma-secretase for the treatment of Alzheimer's disease. Int J Alzheimers Dis. 2012;2012:210756.
• [16] Novel gamma-secretase inhibitors discovered by library screening of in-house synthetic natural product intermediates. Bioorg Med Chem Lett. 2006 Jul 15;16(14):3813-6.
• [17] Discovery of a Subnanomolar helical D-tridecapeptide inhibitor of gamma-secretase. J Med Chem. 2004 Jul 29;47(16):3931-3.