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

General Information of Drug (ID: DML83IW)

• Drug Name: Semagacestat Drug Info
• Synonyms: DAPT; AN-37124; AN-44989; LY-374973; LY-411575; LY-424354; LY-450139; LY-4501395; Gamma-secretase inhibitors (Alzheimer's disease), Elan Pharmaceuticals/Eli Lilly

Indication

Disease Entry	ICD 11	Status	REF
Parkinson disease	8A00.0	Phase 3	[1]

• Cross-matching ID:
  PubChem CID: 9843750
  ChEBI ID: CHEBI:131158
  CAS Number: CAS 425386-60-3
  TTD Drug ID: DML83IW
  INTEDE Drug ID: DR1888

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	[4]
(S)-FLURBIPROFEN	DMF2O4T	Myalgia	FB56.2	Preregistration	[5]
AMG 386	DMQJXL4	Breast cancer	2C60-2C65	Phase 3	[6]
R-flurbiprofen	DMFIVSR	N. A.	N. A.	Phase 2	[5]
MK-0752	DMLTAES	Alzheimer disease	8A20	Phase 2	[7]
BMS-708163	DM51LTG	Alzheimer disease	8A20	Phase 2	[8]
CHF-5074	DMTE071	Alzheimer disease	8A20	Phase 2	[9]
RO-4929097	DMXA6B3	Breast cancer	2C60-2C65	Phase 2	[10]
AL102	DMCTWIB	Desmoid tumour	2F7C	Phase 2	[11]
SPI-014	DM5IPUS	Alzheimer disease	8A20	Phase 1	[12]

Drug(s) Metabolized By Cytochrome P450 3A4 (CYP3A4)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Doxorubicin	DMVP5YE	Acute myelogenous leukaemia	2A41	Approved	[13]
Progesterone	DMUY35B	Amenorrhea	GA20.0	Approved	[14]
Tamoxifen	DMLB0EZ	Breast cancer	2C60-2C65	Approved	[15]
Estradiol	DMUNTE3	Acne vulgaris	ED80	Approved	[16]
Acetaminophen	DMUIE76	Allergic rhinitis	CA08.0	Approved	[17]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[18]
Etoposide	DMNH3PG	Acute myelogenous leukaemia	2A41	Approved	[19]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[20]
Prasterone	DM67VKL	Chronic obstructive pulmonary disease	CA22	Approved	[14]
Verapamil	DMA7PEW	Angina pectoris	BA40	Approved	[21]

Drug(s) Metabolized By Cytochrome P450 3A5 (CYP3A5)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Doxorubicin	DMVP5YE	Acute myelogenous leukaemia	2A41	Approved	[22]
Progesterone	DMUY35B	Amenorrhea	GA20.0	Approved	[23]
Tamoxifen	DMLB0EZ	Breast cancer	2C60-2C65	Approved	[24]
Estradiol	DMUNTE3	Acne vulgaris	ED80	Approved	[25]
Acetaminophen	DMUIE76	Allergic rhinitis	CA08.0	Approved	[26]
Sulfasalazine	DMICA9H	Irritable bowel syndrome	DD91.0	Approved	[27]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[28]
Etoposide	DMNH3PG	Acute myelogenous leukaemia	2A41	Approved	[29]
Verapamil	DMA7PEW	Angina pectoris	BA40	Approved	[30]
Sorafenib	DMS8IFC	Adenocarcinoma	2D40	Approved	[25]

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	[2]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[3]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Substrate	[3]

References

• [1] 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: 6978).
• [2] A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013 Jul 25;369(4):341-50.
• [3] Disposition and metabolism of semagacestat, a {gamma}-secretase inhibitor, in humans. Drug Metab Dispos. 2010 Apr;38(4):554-65.
• [4] Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014.J Pharmacol Exp Ther.2010 Jul;334(1):269-77.
• [5] 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.
• [6] Clinical pipeline report, company report or official report of Roche (2009).
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Clinical pipeline report, company report or official report of Ayala Pharmaceuticals.
• [12] Modulation of gamma-secretase for the treatment of Alzheimer's disease. Int J Alzheimers Dis. 2012;2012:210756.
• [13] Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
• [14] Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
• [15] Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
• [16] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [17] Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
• [18] Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
• [19] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [20] The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
• [21] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [22] Drug related genetic polymorphisms affecting adverse reactions to methotrexate, vinblastine, doxorubicin and cisplatin in patients with urothelial cancer. J Urol. 2008 Dec;180(6):2389-95.
• [23] Human prostate CYP3A5: identification of a unique 5'-untranslated sequence and characterization of purified recombinant protein. Biochem Biophys Res Commun. 1999 Jul 14;260(3):676-81.
• [24] Polymorphisms in cytochrome P4503A5 (CYP3A5) may be associated with race and tumor characteristics, but not metabolism and side effects of tamoxifen in breast cancer patients. Cancer Lett. 2005 Jan 10;217(1):61-72.
• [25] Drug Interactions Flockhart Table
• [26] Induction of hepatic CYP2E1 by a subtoxic dose of acetaminophen in rats: increase in dichloromethane metabolism and carboxyhemoglobin elevation. Drug Metab Dispos. 2007 Oct;35(10):1754-8.
• [27] Urinary 6 beta-hydroxycortisol excretion in rheumatoid arthritis. Br J Rheumatol. 1997 Jan;36(1):54-8.
• [28] Clinical pharmacokinetics of imatinib. Clin Pharmacokinet. 2005;44(9):879-94.
• [29] Kinetics and regulation of cytochrome P450-mediated etoposide metabolism. Drug Metab Dispos. 2004 Sep;32(9):993-1000.
• [30] Differential mechanism-based inhibition of CYP3A4 and CYP3A5 by verapamil. Drug Metab Dispos. 2005 May;33(5):664-71.