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

General Information of Drug (ID: DM2R86O)

• Drug Name: Siponimod Drug Info
• Synonyms: BAF312

Indication

Disease Entry	ICD 11	Status	REF
Multiple sclerosis	8A40	Approved	[1]
Hepatocellular carcinoma	2C12.02	Phase 3	[2]
Rheumatoid arthritis	FA20	Phase 2	[3]

• Cross-matching ID:
  PubChem CID: 44599207
  CAS Number: CAS 1230487-00-9
  TTD Drug ID: DM2R86O
  VARIDT Drug ID: DR00743
  INTEDE Drug ID: DR1488
  ACDINA Drug ID: D01430

Molecule-Related Drug Atlas

Drug(s) Targeting Sphingosine-1-phosphate receptor 1 (S1PR1)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Fingolimod	DM5JVAN	Multiple sclerosis	8A40	Approved	[5]
Ozanimod	DMT6AM2	Multiple sclerosis	8A40	Approved	[6]
Etrasimod	DMT0A3Y	Ulcerative colitis	DD71	Approved	[3]
Ponesimod	DMEAOYJ	Multiple sclerosis	8A40	Approved	[7]
MT-1303	DMSE9TH	Crohn disease	DD70	Phase 2	[8]
ONO-4641	DMLUM3Y	Rheumatoid arthritis	FA20	Phase 2	[9]
KRP-203	DMOW9X2	Cutaneous lupus erythematosus	EB5Z	Phase 2	[9]
VTX-002	DMZ8Z5A	Ulcerative colitis	DD71	Phase 2	[10]
CBP-307	DM3TH6Y	Ulcerative colitis	DD71	Phase 2	[11]
Sphingosine-1-phosphate	DMJCQKA	Acne vulgaris	ED80	Phase 1	[12]

Drug(s) Targeting Sphingosine-1 phosphate receptor (S1PR)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
KPP203	DM4WHOS	Subacute cutaneous lupus erythematosus	EB50	Phase 2	[3]

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 2C9 (CYP2C9)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Progesterone	DMUY35B	Amenorrhea	GA20.0	Approved	[22]
Tamoxifen	DMLB0EZ	Breast cancer	2C60-2C65	Approved	[23]
Estradiol	DMUNTE3	Acne vulgaris	ED80	Approved	[24]
Acetaminophen	DMUIE76	Allergic rhinitis	CA08.0	Approved	[25]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[26]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[25]
Verapamil	DMA7PEW	Angina pectoris	BA40	Approved	[27]
Diclofenac	DMPIHLS	Chronic renal failure	GB61.Z	Approved	[28]
Estrone	DM5T6US	Acne vulgaris	ED80	Approved	[29]
Valproate	DMCFE9I	Epilepsy	8A60-8A68	Approved	[30]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Sphingosine-1 phosphate receptor (S1PR)	TT7BQRM	NOUNIPROTAC	Modulator	[1]
Sphingosine-1-phosphate receptor 1 (S1PR1)	TT9JZCK	S1PR1_HUMAN	Modulator	[1]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[4]
Cytochrome P450 2C9 (CYP2C9) Main DME	DE5IED8	CP2C9_HUMAN	Substrate	[4]

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [2] ClinicalTrials.gov (NCT01665144) Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND). U.S. National Institutes of Health.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Metabolism and disposition of siponimod, a novel selective S1P1/S1P5 agonist, in healthy volunteers and in vitro identification of human cytochrome P450 enzymes involved in its oxidative metabolism. Drug Metab Dispos. 2018 Jul;46(7):1001-1013.
• [5] Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5.
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [7] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2021
• [8] Sphingosine 1-Phosphate Receptor Modulators in Multiple Sclerosis. CNS Drugs. 2015 Jul;29(7):565-75.
• [9] Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond. Nat Rev Drug Discov. 2013 Sep;12(9):688-702.
• [10] Clinical pipeline report, company report or official report of Ventyx Biosciences
• [11] Clinical pipeline report, company report or official report of Connect Biopharma
• [12] Exploration of amino alcohol derivatives as novel, potent, and highly selective sphingosine-1-phosphate receptor subtype-1 agonists. Bioorg Med Chem Lett. 2010 Apr 15;20(8):2520-4.
• [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] Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes. Arch Biochem Biophys. 1997 Oct 1;346(1):161-9.
• [23] Tamoxifen inhibits cytochrome P450 2C9 activity in breast cancer patients. J Chemother. 2006 Aug;18(4):421-4.
• [24] Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology. 2003 Aug;144(8):3382-98.
• [25] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [26] Drug-drug interactions with imatinib: an observational study. Medicine (Baltimore). 2016 Oct;95(40):e5076.
• [27] Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A. Drug Metab Dispos. 2000 Feb;28(2):125-30.
• [28] New insights into the structural features and functional relevance of human cytochrome P450 2C9. Part I. Curr Drug Metab. 2009 Dec;10(10):1075-126.
• [29] A potential role for the estrogen-metabolizing cytochrome P450 enzymes in human breast carcinogenesis. Breast Cancer Res Treat. 2003 Dec;82(3):191-7.
• [30] A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother. 1998 May;32(5):554-63.