Details of the Drug-Related molecule(s) Interaction Atlas

General Information of Drug (ID: DMTE071)

• Drug Name: CHF-5074 Drug Info
• Synonyms: CHF 5074; CHF5074; 749269-83-8; CHF-5074; Itanapraced; UNII-C35RF1MWQZ; GHF-5074; C35RF1MWQZ; CHEMBL196945; 1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid; 1-[4-(3,4-dichlorophenyl)-3-fluorophenyl]cyclopropane-1-carboxylic acid; 1-(3',4'-Dichloro-2-Fluorobiphenyl-4-Yl)cyclopropanecarboxylic Acid; H50; SCHEMBL407631; GTPL7339; DTXSID30225901; AOB5325; LIYLTQQDABRNRX-UHFFFAOYSA-N; ZINC3986651; EX-A1963; BDBM50172482; AKOS026750398; SB16945; CS-5022; NCGC00408905-01; AS-16850; HY-14399; BC600569; FT-0708261

Indication

Disease Entry	ICD 11	Status	REF
Alzheimer disease	8A20	Phase 2	[1]
Cognitive impairment	6D71	Phase 2	[2]

• Cross-matching ID:
  PubChem CID: 9996409
  CAS Number: CAS 749269-83-8
  TTD Drug ID: DMTE071

Molecule-Related Drug Atlas

Drug(s) Targeting Gamma-secretase (GS)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Nirogacestat	DMUP5Z0	Desmoid tumour	2F7C	Approved	[5]
(S)-FLURBIPROFEN	DMF2O4T	Myalgia	FB56.2	Preregistration	[6]
AMG 386	DMQJXL4	Breast cancer	2C60-2C65	Phase 3	[7]
Semagacestat	DML83IW	Parkinson disease	8A00.0	Phase 3	[8]
R-flurbiprofen	DMFIVSR	N. A.	N. A.	Phase 2	[6]
MK-0752	DMLTAES	Alzheimer disease	8A20	Phase 2	[9]
BMS-708163	DM51LTG	Alzheimer disease	8A20	Phase 2	[10]
RO-4929097	DMXA6B3	Breast cancer	2C60-2C65	Phase 2	[11]
AL102	DMCTWIB	Desmoid tumour	2F7C	Phase 2	[12]
SPI-014	DM5IPUS	Alzheimer disease	8A20	Phase 1	[13]

Drug(s) Affected By Amyloid-beta precursor protein (APP)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Hydrogen peroxide	DM1NG5W	Infectious disease	1A00-CA43.1	Approved	[14]
Selenium	DM25CGV	N. A.	N. A.	Approved	[15]
Methotrexate	DM2TEOL	Anterior urethra cancer		Approved	[16]
Simvastatin	DM30SGU	Arteriosclerosis	BD40	Approved	[17]
Troglitazone	DM3VFPD	Diabetic complication	5A2Y	Approved	[18]
Penicillamine	DM40EF6	Cystinuria	5C60.2	Approved	[19]
Tretinoin	DM49DUI	Acne vulgaris	ED80	Approved	[20]
Isoniazid	DM5JVS3	Latent tuberculosis infection		Approved	[21]
Arsenic trioxide	DM61TA4	Acute lymphoblastic leukaemia	2A85	Approved	[22]
Aluminium	DM6ECN9	Hyperhidrosis	EE00	Approved	[23]

Drug(s) Affected By Prostaglandin G/H synthase 1 (PTGS1)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Rofecoxib	DM3P5DA	Osteoarthritis	FA00-FA05	Approved	[24]
Valproate	DMCFE9I	Epilepsy	8A60-8A68	Approved	[25]
Flupentixol	DM0DJ9O	Schizophrenia	6A20	Approved	[26]
Quercetin	DM3NC4M	Obesity	5B81	Approved	[27]
Troglitazone	DM3VFPD	Diabetic complication	5A2Y	Approved	[28]
Penicillamine	DM40EF6	Cystinuria	5C60.2	Approved	[29]
Tretinoin	DM49DUI	Acne vulgaris	ED80	Approved	[30]
Bupivacaine	DM4PRFC	Anaesthesia	9A78.6	Approved	[31]
Isotretinoin	DM4QTBN	Acne vulgaris	ED80	Approved	[30]
Panobinostat	DM58WKG	Chronic graft versus host disease		Approved	[32]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Gamma-secretase (GS)	TT9W8GU	APH1A_HUMAN; APH1B_HUMAN; PEN2_HUMAN; NICA_HUMAN; PSN1_HUMAN	Modulator	[3]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Amyloid-beta precursor protein (APP)	OTKFD7R4	A4_HUMAN	Protein Interaction/Cellular Processes	[4]
Prostaglandin G/H synthase 1 (PTGS1)	OTHCRLEC	PGH1_HUMAN	Gene/Protein Processing	[4]

References

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• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] 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.
• [4] In vitro and in vivo profiling of CHF5022 and CHF5074 Two beta-amyloid1-42 lowering agents. Pharmacol Res. 2007 Apr;55(4):318-28.
• [5] Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014.J Pharmacol Exp Ther.2010 Jul;334(1):269-77.
• [6] 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.
• [7] Clinical pipeline report, company report or official report of Roche (2009).
• [8] A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013 Jul 25;369(4):341-50.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Clinical pipeline report, company report or official report of Ayala Pharmaceuticals.
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• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [17] Simvastatin protects neurons from cytotoxicity by up-regulating Bcl-2 mRNA and protein. J Neurochem. 2007 Apr;101(1):77-86. doi: 10.1111/j.1471-4159.2006.04375.x. Epub 2007 Jan 4.
• [18] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [19] Chelation and intercalation: complementary properties in a compound for the treatment of Alzheimer's disease. J Struct Biol. 2000 Jun;130(2-3):209-16. doi: 10.1006/jsbi.2000.4285.
• [20] Increased processing of APLP2 and APP with concomitant formation of APP intracellular domains in BDNF and retinoic acid-differentiated human neuroblastoma cells. J Neurochem. 2005 Nov;95(4):1059-68. doi: 10.1111/j.1471-4159.2005.03440.x. Epub 2005 Sep 7.
• [21] Comparison of base-line and chemical-induced transcriptomic responses in HepaRG and RPTEC/TERT1 cells using TempO-Seq. Arch Toxicol. 2018 Aug;92(8):2517-2531.
• [22] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [23] Synergistic effects of iron and aluminum on stress-related gene expression in primary human neural cells. J Alzheimers Dis. 2005 Nov;8(2):117-27; discussion 209-15. doi: 10.3233/jad-2005-8204.
• [24] Acetaminophen selectively suppresses peripheral prostaglandin E2 release and increases COX-2 gene expression in a clinical model of acute inflammation. Pain. 2007 Jun;129(3):279-86.
• [25] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [26] Mitochondrial involvement in schizophrenia and other functional psychoses. Neurochem Res. 1996 Sep;21(9):995-1004.
• [27] Quercetin reduces oxidative damage induced by paraquat via modulating expression of antioxidant genes in A549 cells. J Appl Toxicol. 2013 Dec;33(12):1460-7. doi: 10.1002/jat.2812. Epub 2012 Sep 20.
• [28] Increased sensitivity for troglitazone-induced cytotoxicity using a human in vitro co-culture model. Toxicol In Vitro. 2009 Oct;23(7):1387-95.
• [29] D-Penicillamine targets metastatic melanoma cells with induction of the unfolded protein response (UPR) and Noxa (PMAIP1)-dependent mitochondrial apoptosis. Apoptosis. 2012 Oct;17(10):1079-94.
• [30] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [31] The differential effects of bupivacaine and lidocaine on prostaglandin E2 release, cyclooxygenase gene expression and pain in a clinical pain model. Anesth Analg. 2008 Jan;106(1):321-7, table of contents.
• [32] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.