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

General Information of Drug (ID: DMCXRZF)

• Drug Name: LY2603618 Drug Info
• Synonyms: LY2603618; Rabusertib; 911222-45-2; LY 2603618; LY-2603618; UNII-3S9L1NU6U7; 3S9L1NU6U7; IC-83; ly2603618 IC-83; (S)-1-(5-bromo-4-methyl-2-(morpholin-2-ylmethoxy)phenyl)-3-(5-methylpyrazin-2-yl)urea; n-(5-bromo-4-methyl-2-((2s)-2-morpholinylmethoxy)phenyl)-n'-(5-methyl-2-pyrazinyl)urea; LY2603618 (IC-83); Rabusertib [USAN:INN]; 3-(5-Bromo-4-methyl-2-[(2s)-morpholin-2-ylmethoxy]phenyl)-1-(5-methylpyrazin-2-yl)urea; N-[5-Bromo-4-methyl-2-[(2S)-2-morpholinylmethoxy)phenyl]-N'-(5-methyl-2-pyrazinyl)urea

Indication

Disease Entry	ICD 11	Status	REF
Pancreatic cancer	2C10	Phase 2	[1]

• Cross-matching ID:
  PubChem CID: 11955855
  ChEBI ID: CHEBI:124917
  CAS Number: CAS 911222-45-2
  TTD Drug ID: DMCXRZF
  INTEDE Drug ID: DR1846

Molecule-Related Drug Atlas

Drug(s) Targeting Checkpoint kinase-1 (CHK1)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
UCN-01	DMUNJZB	Non-small-cell lung cancer	2C25.Y	Phase 2	[4]
SCH-900776	DM67EMK	Solid tumour/cancer	2A00-2F9Z	Phase 2	[5]
LY2606368	DM4XMF7	Ovarian cancer	2C73	Phase 2	[6]
LY2880070	DMADEHZ	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[7]
RG7741	DMK6P9J	Lymphoma	2A80-2A86	Phase 1	[8]
GDC-0425	DMDZ26X	Lymphoma	2A80-2A86	Phase 1	[9]
AZD7762	DM1FW0C	Solid tumour/cancer	2A00-2F9Z	Phase 1	[10]
MK-8776	DMAS1RB	Hodgkin lymphoma	2B30	Phase 1	[11]
Diamidothiazole derivative 1	DM02V5Q	N. A.	N. A.	Patented	[12]
XL844	DMHTG38	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1	[13]

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	[14]
Progesterone	DMUY35B	Amenorrhea	GA20.0	Approved	[15]
Tamoxifen	DMLB0EZ	Breast cancer	2C60-2C65	Approved	[16]
Estradiol	DMUNTE3	Acne vulgaris	ED80	Approved	[17]
Acetaminophen	DMUIE76	Allergic rhinitis	CA08.0	Approved	[18]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[19]
Etoposide	DMNH3PG	Acute myelogenous leukaemia	2A41	Approved	[20]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[21]
Prasterone	DM67VKL	Chronic obstructive pulmonary disease	CA22	Approved	[15]
Verapamil	DMA7PEW	Angina pectoris	BA40	Approved	[22]

Drug(s) Metabolized By Cytochrome P450 2D6 (CYP2D6)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Doxorubicin	DMVP5YE	Acute myelogenous leukaemia	2A41	Approved	[23]
Progesterone	DMUY35B	Amenorrhea	GA20.0	Approved	[24]
Tamoxifen	DMLB0EZ	Breast cancer	2C60-2C65	Approved	[25]
Acetaminophen	DMUIE76	Allergic rhinitis	CA08.0	Approved	[18]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[22]
Quinine	DMSWYF5	Malaria	1F40-1F45	Approved	[26]
Propofol	DMB4OLE	Anaesthesia	9A78.6	Approved	[27]
Dopamine	DMPGUCF	Acromegaly	5A60.0	Approved	[28]
Nicotine	DMWX5CO	Lung cancer	2C25.0	Approved	[29]
Propranolol	DM79NTF	Angina pectoris	BA40	Approved	[30]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Checkpoint kinase-1 (CHK1)	TTTU902	CHK1_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 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Substrate	[3]

References

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• [2] Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor. Invest New Drugs. 2014 Apr;32(2):213-26.
• [3] Disposition and metabolism of LY2603618, a Chk-1 inhibitor following intravenous administration in patients with advanced and/or metastatic solid tumors. Xenobiotica. 2014 Sep;44(9):827-41.
• [4] Characterization of an inhibitory dynamic pharmacophore for the ERCC1-XPA interaction using a combined molecular dynamics and virtual screening app... J Mol Graph Model. 2009 Sep;28(2):113-30.
• [5] Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening. Mol Cancer Ther. 2011 Apr;10(4):591-602.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] A phase Ib study of oral Chk1 inhibitor LY2880070 in combination with gemcitabine in patients with advanced or metastatic cancer. Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 3581-3581.
• [8] National Cancer Institute Drug Dictionary (drug id 730054).
• [9] Quantitative assessment of BCL-2:BIM complexes as a pharmacodynamic marker for venetoclax (ABT-199).
• [10] Clinical pipeline report, company report or official report of AstraZeneca (2009).
• [11] Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells. Int J Mol Sci. 2019 Aug 22;20(17):4095.
• [12] Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70.
• [13] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [14] 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.
• [15] Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
• [16] 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.
• [17] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [18] 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.
• [19] 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.
• [20] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [21] 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.
• [22] 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.
• [23] Inhibitory effects of anticancer drugs on dextromethorphan-O-demethylase activity in human liver microsomes. Cancer Chemother Pharmacol. 1993;32(6):491-5.
• [24] Effect of genetic polymorphism on the metabolism of endogenous neuroactive substances, progesterone and p-tyramine, catalyzed by CYP2D6. Brain Res Mol Brain Res. 2004 Oct 22;129(1-2):117-23.
• [25] CYP2D6 polymorphisms and tamoxifen metabolism: clinical relevance. Curr Oncol Rep. 2010 Jan;12(1):7-15.
• [26] Inhibition of cytochrome P450 2D6: structure-activity studies using a series of quinidine and quinine analogues. Chem Res Toxicol. 2003 Apr;16(4):450-9.
• [27] Effects of propofol on human hepatic microsomal cytochrome P450 activities. Xenobiotica. 1998 Sep;28(9):845-53.
• [28] Pharmacogenetics of schizophrenia. Am J Med Genet. 2000 Spring;97(1):98-106.
• [29] Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes. Arch Toxicol. 1999 Mar;73(2):65-70.
• [30] Structure-activity relationship for human cytochrome P450 substrates and inhibitors. Drug Metab Rev. 2002 Feb-May;34(1-2):69-82.