Details of the Drug

General Information of Drug (ID: DMUP5Z0)

• Drug Name: PF-03084014
• Synonyms: Nirogacestat; 1290543-63-3; PF-03084014; PF-3084014; UNII-QZ62892OFJ; 865773-15-5; PF 3084014; PF-03084014 (PF-3084014); QZ62892OFJ; Z-3181; PF03084014; Nirogacestat [USAN]; Nirogacestat (USAN/INN); GTPL7746; SCHEMBL13184754; CHEMBL1770916; EX-A855; DTXSID60235679; MolPort-039-193-852; (2S)-2-[[(2S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]amino]-N-[1-[1-(2,2-dimethylpropylamino)-2-methylpropan-2-yl]imidazol-4-yl]pentanamide; ZINC38217837; s8018; AKOS030526383; SB16726; DB12005; CS-1689; NCGC00378713-01

Indication

Disease Entry	ICD 11	Status	REF
Desmoid tumour	2F7C	Phase 3	[1]
Alzheimer disease	8A20	Phase 2	[2], [3]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[4]

• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 1:
  Molecular Weight (mw); 489.6
  Topological Polar Surface Area (xlogp); 4.8
  Rotatable Bond Count (rotbonds); 11
  Hydrogen Bond Donor Count (hbonddonor); 3
  Hydrogen Bond Acceptor Count (hbondacc); 6
• Chemical Identifiers:
  Formula: C27H41F2N5O
  IUPAC Name: (2S)-2-[[(2S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]amino]-N-[1-[1-(2,2-dimethylpropylamino)-2-methylpropan-2-yl]imidazol-4-yl]pentanamide
  Canonical SMILES: CCC[C@@H](C(=O)NC1=CN(C=N1)C(C)(C)CNCC(C)(C)C)N[C@H]2CCC3=C(C2)C(=CC(=C3)F)F
  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
  InChIKey: VFCRKLWBYMDAED-REWPJTCUSA-N
• Cross-matching ID:
  PubChem CID: 46224413
  CAS Number: 1290543-63-3
  DrugBank ID: DB12005
  TTD ID: D00GPQ

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Amyloid beta A4 protein (APP)	TTE4KHA	A4_HUMAN	Inhibitor	[4]
Gamma-secretase (GS)	TT9W8GU	APH1A_HUMAN; APH1B_HUMAN; PEN2_HUMAN; NICA_HUMAN; PSN1_HUMAN	Modulator	[5]

Molecular Expression Atlas of This Drug

• The Studied Disease: Desmoid tumour
• ICD Disease Classification: 2F7C

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Amyloid beta A4 protein (APP)	DTT	APP	1.60E-02	-0.07	-0.31
Gamma-secretase (GS)	DTT	APH1A; APH1B; NCSTN; PSENEN; PSEN1	1.47E-02	-0.09	-0.37

References

• [1] ClinicalTrials.gov (NCT03785964) Nirogacestat for Adults With Desmoid Tumor/Aggressive Fibromatosis (DT/AF) (DeFi). U.S. National Institutes of Health.
• [2] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7746).
• [3] ClinicalTrials.gov (NCT02299635) A Study Evaluating PF-03084014 In Patients With Advanced Breast Cancer With Or Without Notch Alterations. U.S. National Institutes of Health.
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014.J Pharmacol Exp Ther.2010 Jul;334(1):269-77.
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [7] Curcumin and dehydrozingerone derivatives: synthesis, radiolabeling, and evaluation for beta-amyloid plaque imaging. J Med Chem. 2006 Oct 5;49(20):6111-9.
• [8] Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014 Jan 23;370(4):311-21.
• [9] Passive anti-amyloid immunotherapy in Alzheimer's disease: What are the most promising targets . Immun Ageing. 2013; 10: 18.
• [10] Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain amyloidosis. Neurobiol Aging. 2007 Apr;28(4):537-47.
• [11] Bapineuzumab: anti-beta-amyloid monoclonal antibodies for the treatment of Alzheimer's disease. Immunotherapy. 2010 Nov;2(6):767-82.
• [12] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [13] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [14] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2402).
• [15] Disease-modifying drugs in Alzheimer's disease. Drug Des Devel Ther. 2013; 7: 1471-1479.
• [16] 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.
• [17] Clinical pipeline report, company report or official report of Roche (2009).
• [18] A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013 Jul 25;369(4):341-50.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Clinical pipeline report, company report or official report of Ayala Pharmaceuticals.
• [24] Modulation of gamma-secretase for the treatment of Alzheimer's disease. Int J Alzheimers Dis. 2012;2012:210756.