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

General Information of Drug (ID: DMYLT67)

• Drug Name: TKI258 Drug Info
• Synonyms: Dovitinib; 405169-16-6; CHIR-258; TKI-258; Chir 258; 4-Amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one; CHIR258; Dovitinib (TKI-258, CHIR-258); UNII-I35H55G906; CHEMBL522892; 804551-71-1; I35H55G906; TKI 258; 1027263-12-2; (3Z)-4-Amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydro-2H-benzimidazol-2-ylidene]-2(3H)-quinolinone; C21H21FN6O; 4-Amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one

Indication

Disease Entry	ICD 11	Status	REF
Renal cell carcinoma	2C90	Phase 3	[1]
Endometrial cancer	2C76	Phase 2	[2]
Triple negative breast cancer	2C60-2C65	Phase 2	[3]

• Therapeutic Class: Anticancer Agents
• Cross-matching ID:
  PubChem CID: 135611162
  CAS Number: CAS 915769-50-5
  TTD Drug ID: DMYLT67
  INTEDE Drug ID: DR1815

Molecule-Related Drug Atlas

Drug(s) Targeting Platelet-derived growth factor receptor (PDGFR)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[4]
Pazopanib HCl	DM6U9CQ	Renal cell carcinoma	2C90	Approved	[6]
Intedanib	DMSTA36	Colorectal cancer	2B91.Z	Approved	[7]
CT-102	DMB8PF3	Diabetic foot ulcer	BD54	Approved	[8]
Trapidil	DMY67U8	Acute coronary syndrome	BA41	Phase 4	[9]
BAY-57-9352	DMVA5NS	Gastric adenocarcinoma	2B72	Phase 2	[4]
X-82	DMW1NKO	Age-related macular degeneration	9B75.0	Phase 2	[10]
Vorolanib	DMIM1U9	Non-small-cell lung cancer	2C25	Phase 2	[11]
PMID25623274-Compound-WO2014132220C2	DMXEZWP	Pulmonary arterial hypertension	BB01.0	Patented	[12]
PMID25623274-Compound-WO2014132220C1	DMA2IMQ	Pulmonary arterial hypertension	BB01.0	Patented	[12]

Drug(s) Targeting Fibroblast growth factor receptor 3 (FGFR3)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Pemigatinib	DM819JF	Cholangiocarcinoma	2C12.10	Approved	[13]
Trapidil	DMY67U8	Acute coronary syndrome	BA41	Phase 4	[14]
E-3810	DM42PFT	Solid tumour/cancer	2A00-2F9Z	Phase 3	[15]
BMS-582664	DMDAN8H	Hepatocellular carcinoma	2C12.02	Phase 3	[4]
Debio 1347	DMZW50O	Solid tumour/cancer	2A00-2F9Z	Phase 2	[16]
B-701	DMOMDA4	Bladder cancer	2C94	Phase 2	[17]
Recifercept	DML8N3Y	Achondroplasia	LD24.00	Phase 2	[18]
MK-2461	DM21WBH	Alzheimer disease	8A20	Phase 1/2	[19]
AEE-788	DMEOS5K	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[4]
Anti-FGFR3	DM6QENU	Multiple myeloma	2A83	Phase 1	[20]

Drug(s) Metabolized By Cytochrome P450 1A2 (CYP1A2)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Fluorouracil	DMUM7HZ	Adenocarcinoma	2D40	Approved	[21]
Dinoprostone	DMTYOPD	Medical abortion	JA00.1Z	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]
Etoposide	DMNH3PG	Acute myelogenous leukaemia	2A41	Approved	[27]
Oxaliplatin	DMQNWRD	Adenocarcinoma	2D40	Approved	[28]
Verapamil	DMA7PEW	Angina pectoris	BA40	Approved	[29]
Diclofenac	DMPIHLS	Chronic renal failure	GB61.Z	Approved	[30]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Fibroblast growth factor receptor 3 (FGFR3)	TTST7KB	FGFR3_HUMAN	Inhibitor	[4]
Platelet-derived growth factor receptor (PDGFR)	TTI2WET	NOUNIPROTAC	Inhibitor	[4]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 1A2 (CYP1A2) Main DME	DEJGDUW	CP1A2_HUMAN	Substrate	[5]

References

• [1] ClinicalTrials.gov (NCT01223027) Study of Dovitinib Versus Sorafenib in Patients With Metastatic Renal Cell Carcinoma. U.S. National Institutes of Health.
• [2] Phase 2 study of dovitinib in patients with metastatic or unresectable adenoid cystic carcinoma. Cancer. 2015 Aug 1;121(15):2612-7.
• [3] ClinicalTrials.gov (NCT01262027) TKI258 for Metastatic Inflammatory Breast Cancer Patients. U.S. National Institutes of Health.
• [4] A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
• [5] A drug-drug interaction study to assess the effect of the CYP1A2 inhibitor fluvoxamine on the pharmacokinetics of dovitinib (TKI258) in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2018 Jan;81(1):73-80.
• [6] Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
• [7] 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
• [8] Emerging drugs for diabetic foot ulcers. Expert Opin Emerg Drugs. 2006 Nov;11(4):709-24.
• [9] Osteitis fibrosa is mediated by Platelet-Derived Growth Factor-A via a phosphoinositide 3-kinase-dependent signaling pathway in a rat model for chr... Endocrinology. 2008 Nov;149(11):5735-46.
• [10] National Cancer Institute Drug Dictionary (drug id 695817).
• [11] Vorolanib, an oral VEGFR/PDGFR dual tyrosine kinase inhibitor for treatment of patients with advanced solid tumors: An open-label, phase I dose escalation and dose expansion trial. Chin J Cancer Res. 2021 Feb 28;33(1):103-114.
• [12] Evaluation of WO-2014132220, selective PDGFR inhibitors for the treatment of pulmonary arterial hypertension.Expert Opin Ther Pat. 2015 Apr;25(4):493-9.
• [13] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [14] Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
• [15] E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Res. 2011 Feb 15;71(4):1396-405.
• [16] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [17] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [18] In vitro and in vivo characterization of Recifercept, a soluble fibroblast growth factor receptor 3, as treatment for achondroplasia. PLoS One. 2020 Dec 28;15(12):e0244368.
• [19] MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
• [20] Clinical pipeline report, company report or official report of Genentech (2011).
• [21] Roles of cytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, an anticancer prodrug, in human liver microsomes. Drug Metab Dispos. 2000 Dec;28(12):1457-63.
• [22] Effects of polyunsaturated fatty acids on prostaglandin synthesis and cyclooxygenase-mediated DNA adduct formation by heterocyclic aromatic amines in human adenocarcinoma colon cells. Mol Carcinog. 2004 Jul;40(3):180-8.
• [23] Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50.
• [24] Cytochrome P450 1A2 (CYP1A2) activity and risk factors for breast cancer: a cross-sectional study. Breast Cancer Res. 2004;6(4):R352-65.
• [25] PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics. 2015 Aug;25(8):416-26.
• [26] The effect of apigenin on pharmacokinetics of imatinib and its metabolite N-desmethyl imatinib in rats. Biomed Res Int. 2013;2013:789184.
• [27] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [28] 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.
• [29] Identification of P450 enzymes involved in metabolism of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1993 Sep;348(3):332-7.
• [30] Metabolism and metabolic inhibition of xanthotoxol in human liver microsomes. Evid Based Complement Alternat Med. 2016;2016:5416509.