Details of the Drug

General Information of Drug (ID: DM3WP0N)

• Drug Name: Al3818
• Synonyms: Anlotinib; 1058156-90-3; UNII-GKF8S4C432; GKF8S4C432; AL-3818; SCHEMBL2063386; GTPL9601; KSMZEXLVHXZPEF-UHFFFAOYSA-N; MolPort-044-567-604; ZINC117924202; AKOS030526233; DB11885; CS-5396; AL 3818; HY-19716; 1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinolin-7-yl]oxymethyl]cyclopropan-1-amine; 1-((4-(4-fluoro-2-methyl-1h-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropan-amine; Cyclopropanamine, 1-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxy-7-quinolinyl)oxy)methyl)-

Indication

Disease Entry	ICD 11	Status	REF
Alveolar soft part sarcoma	2A60-2C35	Phase 3	[1]
Leiomyosarcoma	2B58	Phase 3	[1]
Synovial sarcoma	2B5A	Phase 3	[1]
Cervical cancer	2C77.0	Phase 1/2	[1]
Endometrial cancer	2C76	Phase 1/2	[1]
Fallopian tube cancer	2C74	Phase 1/2	[1]
Ovarian cancer	2C73	Phase 1/2	[1], [2]
Peritoneal cavity cancer	2C51.Z	Phase 1/2	[1]

• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 407.4
  Topological Polar Surface Area (xlogp); 3.7
  Rotatable Bond Count (rotbonds); 6
  Hydrogen Bond Donor Count (hbonddonor); 2
  Hydrogen Bond Acceptor Count (hbondacc); 6
• Chemical Identifiers:
  Formula: C23H22FN3O3
  IUPAC Name: 1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinolin-7-yl]oxymethyl]cyclopropan-1-amine
  Canonical SMILES: CC1=CC2=C(N1)C=CC(=C2F)OC3=C4C=C(C(=CC4=NC=C3)OCC5(CC5)N)OC
  InChI: InChI=1S/C23H22FN3O3/c1-13-9-15-16(27-13)3-4-19(22(15)24)30-18-5-8-26-17-11-21(20(28-2)10-14(17)18)29-12-23(25)6-7-23/h3-5,8-11,27H,6-7,12,25H2,1-2H3
  InChIKey: KSMZEXLVHXZPEF-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 25017411
  CAS Number: 1058156-90-3
  DrugBank ID: DB11885
  TTD ID: D0G2CG
  INTEDE ID: DR1881

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Proto-oncogene c-Src (SRC)	TT6PKBN	SRC_HUMAN	Inhibitor	[1]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[3]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Substrate	[3]

Molecular Expression Atlas of This Drug

• The Studied Disease: Alveolar soft part sarcoma
• ICD Disease Classification: 2A60-2C35

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Proto-oncogene c-Src (SRC)	DTT	SRC	6.45E-01	-0.08	-0.58
Proto-oncogene c-Src (SRC)	DTT	SRC	2.08E-03	-0.52	-1.62
Cytochrome P450 3A5 (CYP3A5)	DME	CYP3A5	7.76E-01	-2.05E-01	-5.72E+00
Cytochrome P450 3A5 (CYP3A5)	DME	CYP3A5	9.78E-01	-1.22E-03	-4.10E-03
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	5.50E-01	-9.32E-02	-1.01E+00
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	2.15E-08	-6.60E-01	-3.96E+00

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development. J Hematol Oncol. 2018 Sep 19;11(1):120.
• [4] 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.
• [5] Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
• [6] 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.
• [7] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [8] 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.
• [9] 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.
• [10] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [11] 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.
• [12] 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.
• [13] Drug related genetic polymorphisms affecting adverse reactions to methotrexate, vinblastine, doxorubicin and cisplatin in patients with urothelial cancer. J Urol. 2008 Dec;180(6):2389-95.
• [14] Human prostate CYP3A5: identification of a unique 5'-untranslated sequence and characterization of purified recombinant protein. Biochem Biophys Res Commun. 1999 Jul 14;260(3):676-81.
• [15] Polymorphisms in cytochrome P4503A5 (CYP3A5) may be associated with race and tumor characteristics, but not metabolism and side effects of tamoxifen in breast cancer patients. Cancer Lett. 2005 Jan 10;217(1):61-72.
• [16] Drug Interactions Flockhart Table
• [17] Induction of hepatic CYP2E1 by a subtoxic dose of acetaminophen in rats: increase in dichloromethane metabolism and carboxyhemoglobin elevation. Drug Metab Dispos. 2007 Oct;35(10):1754-8.
• [18] Urinary 6 beta-hydroxycortisol excretion in rheumatoid arthritis. Br J Rheumatol. 1997 Jan;36(1):54-8.
• [19] Clinical pharmacokinetics of imatinib. Clin Pharmacokinet. 2005;44(9):879-94.
• [20] Kinetics and regulation of cytochrome P450-mediated etoposide metabolism. Drug Metab Dispos. 2004 Sep;32(9):993-1000.
• [21] Differential mechanism-based inhibition of CYP3A4 and CYP3A5 by verapamil. Drug Metab Dispos. 2005 May;33(5):664-71.
• [22] 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.
• [23] Synthesis and Src kinase inhibitory activity of a series of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-furyl-3-quinolinecarbonitriles. J Med Chem. 2006 Dec 28;49(26):7868-76.
• [24] In vivo antitumor activity of herbimycin A, a tyrosine kinase inhibitor, targeted against BCR/ABL oncoprotein in mice bearing BCR/ABL-transfected cells. Leuk Res. 1994 Nov;18(11):867-73.
• [25] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [26] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [27] Novel dual Src/Abl inhibitors for hematologic and solid malignancies.Expert Opin Investig Drugs.2010 Aug;19(8):931-45.
• [28] Clinical pipeline report, company report or official report of Turning Point Therapeutics.
• [29] The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315.