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

General Information of Drug (ID: DMLYGH4)

• Drug Name: MK-4827 Drug Info
• Synonyms: 1038915-60-4; (S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide; UNII-HMC2H89N35; HMC2H89N35; CHEMBL1094636; 2-{4-[(3s)-piperidin-3-yl]phenyl}-2h-indazole-7-carboxamide; MK4827; MK 4827; Niraparib [USAN:INN]; 2-{4-[(3S)-piperidin-3-yl]phenyl}indazole-7-carboxamide; 2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide; MK 4827 (Base); Niraparib (USAN); Zejula (TN); MK-4827(Niraparib); SCHEMBL1421875; GTPL8275; CTK8B9123; EX-A290; DTXSID50146129; MolPort-023-219-142; ZINC43206370; BDBM50316226

Indication

Disease Entry	ICD 11	Status	REF
Ovarian cancer	2C73	Phase 3	[1]
Breast cancer	2C60-2C65	Phase 2	[2]
Ewing sarcoma	2B52	Phase 1	[2]

• Cross-matching ID:
  PubChem CID: 24958200
  CAS Number: CAS 1038915-60-4
  TTD Drug ID: DMLYGH4
  INTEDE Drug ID: DR1164
  ACDINA Drug ID: D00471

Molecule-Related Drug Atlas

Drug(s) Targeting Poly [ADP-ribose] polymerase (PARP)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Olaparib	DM8QB1D	Ovarian cancer	2C73	Approved	[7]
Rucaparib	DM9PVX8	Ovarian cancer	2C73	Approved	[8]
Talazoparib	DM1KS78	Breast cancer	2C60-2C65	Approved	[9]
BSI-201	DMM0VO3	Solid tumour/cancer	2A00-2F9Z	Phase 3	[10]
Rubraca rucaparib	DM25TMP	Ovarian cancer	2C73	Phase 3	[2]
ABT-888	DM4HYMS	Breast cancer	2C60-2C65	Phase 3	[3]
INO-1001	DM5L8QT	Brain cancer	2A00	Phase 3	[11]
BGP-15	DMYDM68	Type-2 diabetes	5A11	Phase 2	[12]
BGB-290	DMRO6XT	Ovarian cancer	2C73	Phase 2	[2]
2X-121	DMX9MSL	Breast cancer	2C60-2C65	Phase 2	[2]

Drug(s) Metabolized By Cytochrome P450 1A1 (CYP1A1)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Progesterone	DMUY35B	Amenorrhea	GA20.0	Approved	[13]
Tamoxifen	DMLB0EZ	Breast cancer	2C60-2C65	Approved	[14]
Estradiol	DMUNTE3	Acne vulgaris	ED80	Approved	[15]
Acetaminophen	DMUIE76	Allergic rhinitis	CA08.0	Approved	[16]
Oxaliplatin	DMQNWRD	Adenocarcinoma	2D40	Approved	[17]
Diclofenac	DMPIHLS	Chronic renal failure	GB61.Z	Approved	[18]
Estrone	DM5T6US	Acne vulgaris	ED80	Approved	[19]
Erythromycin	DM4K7GQ	Acne vulgaris	ED80	Approved	[20]
Riboflavin	DM8YMWE	Acne vulgaris	ED80	Approved	[21]
Mercaptopurine	DMTM2IK	Acute lymphoblastic leukaemia	2A85	Approved	[22]

Drug(s) Metabolized By Carboxylesterase 1 (CES1)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Irinotecan	DMP6SC2	Adenocarcinoma	2D40	Approved	[23]
Enalapril	DMNFUZR	Congestive heart failure	BD10	Approved	[24]
Candesartan	DMRK8OT	Chronic heart failure	BD1Z	Approved	[25]
Salbutamol	DMN9CWF	Acute asthma	CA23	Approved	[26]
Methylphenidate	DM7SJD6	Attention deficit hyperactivity disorder	6A05.Z	Approved	[27]
PSI-7977	DMLSUWZ	HCV 1-6 infection	1E51	Approved	[28]
Rufinamide	DMWE60C	Epilepsy	8A60-8A68	Approved	[29]
Dexmethylphenidate	DMUQE2A	Attention deficit hyperactivity disorder	6A05.Z	Approved	[30]
Dabigatran etexilate	DMRDZ4X	Venous thromboembolism	BD72	Phase 3	[31]
Pradaxa	DM2ZYX9	Stroke	8B20	Phase 3	[32]

Drug(s) Metabolized By Beta-glucuronidase (GUSB)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Chondroitin sulfate	DM0N19Y	N. A.	N. A.	Phase 4	[33]
Tyropanoic acid	DM91UKB	N. A.	N. A.	Investigative	[34]

Drug(s) Affected By Histone H2AX (H2AX)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cannabidiol	DM0659E	Dravet syndrome	8A61.11	Approved	[35]
Hydrogen peroxide	DM1NG5W	Infectious disease	1A00-CA43.1	Approved	[36]
Selenium	DM25CGV	N. A.	N. A.	Approved	[37]
Ribavirin	DMEYLH9	Hepatitis C virus infection	1E51.1	Approved	[38]
Etretinate	DM2CZFA	Keratosis	ED56	Approved	[39]
Methotrexate	DM2TEOL	Anterior urethra cancer		Approved	[40]
Dactinomycin	DM2YGNW	Adult kidney Wilms tumor		Approved	[41]
Simvastatin	DM30SGU	Arteriosclerosis	BD40	Approved	[42]
Lapatinib	DM3BH1Y	Breast cancer	2C60-2C65	Approved	[43]
Quercetin	DM3NC4M	Obesity	5B81	Approved	[44]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Poly [ADP-ribose] polymerase (PARP)	TTEBCY8	NOUNIPROTAC	Modulator	[3]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Substrate	[4]
Carboxylesterase 1 (CES1) Main DME	DEB30C5	EST1_HUMAN	Substrate	[5]
Beta-glucuronidase (GUSB)	DEP54UE	BGLR_HUMAN	Substrate	[5]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Gene/Protein Processing	[6]

References

• [1] ClinicalTrials.gov (NCT03602859) A Phase 3 Comparison of Platinum-based Therapy With TSR-042 and Niraparib Versus Standard of Care (SOC) Platinum-based Therapy as First-line Treatment of Stage III or IV Nonmucinous Epithelial Ovarian Cancer (FIRST). U.S. National Institutes of Health.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [4] Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J Med Chem. 2009 Nov 26;52(22):7170-85.
• [5] Summary of FDA-approved anticancer cytotoxic drugs at May 2019.
• [6] Autophagy up-regulated by MEK/ERK promotes the repair of DNA damage caused by aflatoxin B1. Toxicol Mech Methods. 2022 Feb;32(2):87-96. doi: 10.1080/15376516.2021.1968985. Epub 2021 Aug 26.
• [7] 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
• [8] 2016 FDA drug approvals. Nat Rev Drug Discov. 2017 Feb 2;16(2):73-76.
• [9] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [10] Failure of iniparib to inhibit poly(ADP-Ribose) polymerase in vitro. Clin Cancer Res. 2012 Mar 15;18(6):1655-62.
• [11] Therapeutic injection of PARP inhibitor INO-1001 preserves cardiac function in porcine myocardial ischemia and reperfusion without reducing infarct size. Shock. 2010 May;33(5):507-12.
• [12] BGP-15, a PARP-inhibitor, prevents imatinib-induced cardiotoxicity by activating Akt and suppressing JNK and p38 MAP kinases. Mol Cell Biochem. 2012 Jun;365(1-2):129-37.
• [13] Allelic variants of human cytochrome P450 1A1 (CYP1A1): effect of T461N and I462V substitutions on steroid hydroxylase specificity. Pharmacogenetics. 2000 Aug;10(6):519-30.
• [14] Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4'-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos. 2002 Aug;30(8):869-74.
• [15] Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA. Metabolism. 2007 Jul;56(7):887-94.
• [16] Preferred orientations in the binding of 4'-hydroxyacetanilide (acetaminophen) to cytochrome P450 1A1 and 2B1 isoforms as determined by 13C- and 15N-NMR relaxation studies. J Med Chem. 1994 Mar 18;37(6):860-7.
• [17] The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentrations in Chinese coke oven workers. Sci Total Environ. 2007 Aug 1;381(1-3):38-46.
• [18] Diclofenac and its derivatives as tools for studying human cytochromes P450 active sites: particular efficiency and regioselectivity of P450 2Cs. Biochemistry. 1999 Oct 26;38(43):14264-70.
• [19] A common CYP1B1 polymorphism is associated with 2-OHE1/16-OHE1 urinary estrone ratio. Clin Chem Lab Med. 2005;43(7):702-6.
• [20] Cytochromes P450 in crustacea. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1998 Nov;121(1-3):157-72.
• [21] Disruption of endogenous regulator homeostasis underlies the mechanism of rat CYP1A1 mRNA induction by metyrapone. Biochem J. 1998 Apr 1;331 ( Pt 1):273-81.
• [22] Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy. Curr Drug Metab. 2007 Aug;8(6):554-62.
• [23] Irinotecan and its active metabolite, SN-38: review of bioanalytical methods and recent update from clinical pharmacology perspectives. Biomed Chromatogr. 2010 Jan;24(1):104-23.
• [24] Absorption and cleavage of enalapril, a carboxyl ester prodrug, in the rat intestine: in vitro, in situ intestinal perfusion and portal vein cannulation models. Biopharm Drug Dispos. 2015 Sep;36(6):385-397.
• [25] Different hydrolases involved in bioactivation of prodrug-type angiotensin receptor blockers: carboxymethylenebutenolidase and carboxylesterase 1. Drug Metab Dispos. 2013 Nov;41(11):1888-95.
• [26] Effect of carboxylesterase 1 c.428G>A single nucleotide variation on the pharmacokinetics of quinapril and enalapril. Br J Clin Pharmacol. 2015 Nov;80(5):1131-8.
• [27] Methylphenidate is stereoselectively hydrolyzed by human carboxylesterase CES1A1. J Pharmacol Exp Ther. 2004 Aug;310(2):469-76.
• [28] Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J Biol Chem. 2010 Nov 5;285(45):34337-47.
• [29] Investigation of the metabolism of rufinamide and its interaction with valproate. Drug Metab Lett. 2011 Dec;5(4):280-9.
• [30] Dexmethylphenidate hydrochloride in the treatment of attention deficit hyperactivity disorder. Neuropsychiatr Dis Treat. 2006 Dec;2(4):467-73.
• [31] Pharmacogenomics of novel direct oral anticoagulants: newly identified genes and genetic variants. J Pers Med. 2019 Jan 17;9(1). pii: E7.
• [32] Conventional liquid chromatography/triple quadrupole mass spectrometry based metabolite identification and semi-quantitative estimation approach in the investigation of in vitro dabigatran etexilate metabolism. Anal Bioanal Chem. 2013 Feb;405(5):1695-704.
• [33] MFN human ref: Chondroitin sulfate degradation.
• [34] Foreign Compound Metabolism in Mammals. Edited by D. E. Hathway.
• [35] Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration. Oncotarget. 2016 Nov 22;7(47):77543-77557. doi: 10.18632/oncotarget.12721.
• [36] Hsa-let-7g miRNA regulates the anti-tumor effects of gastric cancer cells under oxidative stress through the expression of DDR genes. J Toxicol Sci. 2015 Jun;40(3):329-38. doi: 10.2131/jts.40.329.
• [37] 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.
• [38] Inhibition of cardiomyocyte differentiation of human induced pluripotent stem cells by Ribavirin: Implication for its cardiac developmental toxicity. Toxicology. 2020 Apr 15;435:152422. doi: 10.1016/j.tox.2020.152422. Epub 2020 Feb 26.
• [39] Synthesis and structure-activity relationships of new antiproliferative and proapoptotic retinoid-related biphenyl-4-yl-acrylic acids. Bioorg Med Chem. 2007 Jul 15;15(14):4863-75. doi: 10.1016/j.bmc.2007.04.057. Epub 2007 May 3.
• [40] Methotrexate induces apoptosis through p53/p21-dependent pathway and increases E-cadherin expression through downregulation of HDAC/EZH2. Biochem Pharmacol. 2011 Feb 15;81(4):510-7. doi: 10.1016/j.bcp.2010.11.014. Epub 2010 Nov 27.
• [41] Actinomycin D inhibits the expression of the cystine/glutamate transporter xCT via attenuation of CD133 synthesis in CD133(+) HCC. Chem Biol Interact. 2019 Aug 25;309:108713. doi: 10.1016/j.cbi.2019.06.026. Epub 2019 Jun 19.
• [42] Simvastatin and purine analogs have a synergic effect on apoptosis of chronic lymphocytic leukemia cells. Ann Hematol. 2010 Nov;89(11):1115-24. doi: 10.1007/s00277-010-0988-z. Epub 2010 May 25.
• [43] The involvement of hepatic cytochrome P450s in the cytotoxicity of lapatinib. Toxicol Sci. 2023 Dec 21;197(1):69-78. doi: 10.1093/toxsci/kfad099.
• [44] The isoflavonoids genistein and quercetin activate different stress signaling pathways as shown by analysis of site-specific phosphorylation of ATM, p53 and histone H2AX. DNA Repair (Amst). 2004 Mar 4;3(3):235-44. doi: 10.1016/j.dnarep.2003.10.014.