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

General Information of Drug (ID: DMH1DYU)

• Drug Name: MSC1936369B Drug Info
• Synonyms: Pimasertib; 1236699-92-5; AS703026; AS-703026; Pimasertib (AS-703026); MSC1936369B; UNII-6ON9RK82AL; AS 703026; (S)-N-(2,3-dihydroxypropyl)-3-(2-fluoro-4-iodophenylamino)isonicotinamide; 6ON9RK82AL; N-[(2S)-2,3-Dihydroxypropyl]-3-[(2-fluoro-4-iodophenyl)amino]-4-pyridinecarboxamide; 1204531-26-9; C15H15FIN3O3; N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodo-anilino)pyridine-4-carboxamide; N-((2S)-2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)pyridine-4-carboxamide; Pimasertib [USAN:INN]

Indication

Disease Entry	ICD 11	Status	REF
Colorectal cancer	2B91.Z	Phase 2	[1]

• Cross-matching ID:
  PubChem CID: 44187362
  ChEBI ID: CHEBI:94793
  CAS Number: CAS 1204531-26-9
  TTD Drug ID: DMH1DYU
  INTEDE Drug ID: DR1835

Molecule-Related Drug Atlas

Drug(s) Targeting MAPK/ERK kinase kinase (MAP3K)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ARRY-162	DM1P6FR	Melanoma	2C30	Approved	[4]
Trametinib	DM2JGQ3	Melanoma	2C30	Approved	[5]
BAY 86-9766	DMPW5SB	Solid tumour/cancer	2A00-2F9Z	Phase 3	[6]
Selumetinib	DMC7W6R	Neurofibromatosis type 1	LD2D.10	Phase 3	[7]
RO-5126766	DM3U9BY	Non-small-cell lung cancer	2C25	Phase 2	[8]
E6201	DMOSL9P	Psoriasis vulgaris	EA90	Phase 2	[9]
PD-0325901	DM27D4J	Breast cancer	2C60-2C65	Phase 2	[4]
WX-554	DMRABOS	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[4]
RG7304	DMGFAVQ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[10]
BI-847325	DMY4B6J	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]

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	[12]
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]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[17]
Etoposide	DMNH3PG	Acute myelogenous leukaemia	2A41	Approved	[18]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[19]
Prasterone	DM67VKL	Chronic obstructive pulmonary disease	CA22	Approved	[13]
Verapamil	DMA7PEW	Angina pectoris	BA40	Approved	[20]

Drug(s) Metabolized By Mephenytoin 4-hydroxylase (CYP2C19)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Amoxicillin	DMUYNEI	Acute otitis media	AB00	Approved	[21]
Progesterone	DMUY35B	Amenorrhea	GA20.0	Approved	[22]
Tamoxifen	DMLB0EZ	Breast cancer	2C60-2C65	Approved	[23]
Estradiol	DMUNTE3	Acne vulgaris	ED80	Approved	[24]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[25]
Verapamil	DMA7PEW	Angina pectoris	BA40	Approved	[26]
Diclofenac	DMPIHLS	Chronic renal failure	GB61.Z	Approved	[27]
Valproate	DMCFE9I	Epilepsy	8A60-8A68	Approved	[28]
Quinine	DMSWYF5	Malaria	1F40-1F45	Approved	[29]
Propofol	DMB4OLE	Anaesthesia	9A78.6	Approved	[30]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
MAPK/ERK kinase kinase (MAP3K)	TTROQ37	NOUNIPROTAC	Modulator	[2]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[3]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_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: 7872).
• [2] Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells. Int J Cancer. 2013 Nov;133(9):2089-101.
• [3] Metabolism of the MEK1/2 inhibitor pimasertib involves a novel conjugation with phosphoethanolamine in patients with solid tumors. Drug Metab Dispos. 2017 Feb;45(2):174-182.
• [4] MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013; 6: 27.
• [5] Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
• [6] RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer.Cancer Res.2009 Sep 1;69(17):6839-47.
• [7] Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase A activation in human lung and colorectal cancer cells.Br J Cancer.2012 May 8;106(10):1648-59.
• [8] The dual RAF/MEK inhibitor CH5126766/RO5126766 may be a potential therapy for RAS-mutated tumor cells.PLoS One.2014 Nov 25;9(11):e113217.
• [9] E6201, a novel kinase inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase-1: in vivo effects on cutaneous inflammatory responses by topical administration. J Pharmacol Exp Ther. 2010 Oct;335(1):23-31.
• [10] Clinical pipeline report, company report or official report of Roche.
• [11] doi: 10.1158/1535-7163.TARG-13-B281
• [12] 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.
• [13] Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
• [14] 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.
• [15] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [16] 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.
• [17] 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.
• [18] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [19] 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.
• [20] 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.
• [21] High-dose rabeprazole/amoxicillin therapy as the second-line regimen after failure to eradicate H. pylori by triple therapy with the usual doses of a proton pump inhibitor, clarithromycin and amoxicillin. Hepatogastroenterology. 2003 Nov-Dec;50(54):2274-8.
• [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] Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006 Mar 13;25(11):1679-91.
• [24] CYP2C19*17 is associated with decreased breast cancer risk. Breast Cancer Res Treat. 2009 May;115(2):391-6.
• [25] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [26] Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1995 Dec;353(1):116-21.
• [27] 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.
• [28] A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother. 1998 May;32(5):554-63.
• [29] Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001 Feb;120(2):525-33.
• [30] Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth. 1998 Jun;80(6):788-95.