General Information of Drug (ID: DMW9F1G)

Drug Name
CKD602
Synonyms
Belotecan hydrochloride; 213819-48-8; Belotecan; CKD-602; Belotecan HCl; Camtobell hydrochloride; Belotecan (hydrochloride); CKD 602; UNII-01DZ4127G7; 01DZ4127G7; Belotecan hydrochloride (USAN); Belotecan Hydrochloride [USAN]; CHEMBL2107315; DTXSID60175647; BCP28717; HY-13566A; AKOS027420465; API0009359; CS-6955; (S)-4-ethyl-4-hydroxy-11-(2-(isopropylamino)ethyl)-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione hydrochloride; AN-29684; ACM213819488; FT-0662513; D03225; 819C488; J-014022
Indication
Disease Entry ICD 11 Status REF
Solid tumour/cancer 2A00-2F9Z Phase 2 [1]
Drug Type
Small molecular drug
Structure
3D MOL 2D MOL
#Ro5 Violations (Lipinski): 0 Molecular Weight (mw) 433.5
Topological Polar Surface Area (xlogp) 1.6
Rotatable Bond Count (rotbonds) 5
Hydrogen Bond Donor Count (hbonddonor) 2
Hydrogen Bond Acceptor Count (hbondacc) 6
Chemical Identifiers
Formula
C25H27N3O4
IUPAC Name
(19S)-19-ethyl-19-hydroxy-10-[2-(propan-2-ylamino)ethyl]-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaene-14,18-dione
Canonical SMILES
CC[C@@]1(C2=C(COC1=O)C(=O)N3CC4=C(C5=CC=CC=C5N=C4C3=C2)CCNC(C)C)O
InChI
InChI=1S/C25H27N3O4/c1-4-25(31)19-11-21-22-17(12-28(21)23(29)18(19)13-32-24(25)30)15(9-10-26-14(2)3)16-7-5-6-8-20(16)27-22/h5-8,11,14,26,31H,4,9-10,12-13H2,1-3H3/t25-/m0/s1
InChIKey
LNHWXBUNXOXMRL-VWLOTQADSA-N
Cross-matching ID
PubChem CID
6456014
ChEBI ID
CHEBI:135702
CAS Number
256411-32-2
DrugBank ID
DB12459
TTD ID
D0U6ML
VARIDT ID
DR01439

Molecular Interaction Atlas of This Drug


Drug Therapeutic Target (DTT)
DTT Name DTT ID UniProt ID MOA REF
DNA topoisomerase I (TOP1) TTGTQHC TOP1_HUMAN Inhibitor [2]

Drug Transporter (DTP)
DTP Name DTP ID UniProt ID MOA REF
Multidrug resistance-associated protein 2 (ABCC2) DTFI42L MRP2_HUMAN Substrate [3]
Breast cancer resistance protein (ABCG2) DTI7UX6 ABCG2_HUMAN Substrate [4]
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [3]
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This Drug

Molecular Expression Atlas of This Drug

The Studied Disease Solid tumour/cancer
ICD Disease Classification 2A00-2F9Z
Molecule Name Molecule Type Gene Name p-value Fold-Change Z-score
DNA topoisomerase I (TOP1) DTT TOP1 6.65E-01 0.2 0.39
P-glycoprotein 1 (ABCB1) DTP P-GP 3.12E-33 -8.30E-01 -1.04E+00
Breast cancer resistance protein (ABCG2) DTP BCRP 3.87E-47 -1.28E+00 -1.63E+00
Multidrug resistance-associated protein 2 (ABCC2) DTP MRP2 1.02E-08 -5.12E-02 -2.22E-01
Molecular Expression Atlas (MEA) Jump to Detail Molecular Expression Atlas of This Drug

References

1 ClinicalTrials.gov (NCT00430144) Belotecan (CKD-602) in Recurrent or Progressive Carcinoma of Uterine Cervix. U.S. National Institutes of Health.
2 Antitumor activity of 7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin, CKD602, as a potent DNA topoisomerase I inhibitor. Arch Pharm Res. 1998 Oct;21(5):581-90.
3 Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
4 Involvement of P-glycoprotein, multidrug resistance protein 2 and breast cancer resistance protein in the transport of belotecan and topotecan in Caco-2 and MDCKII cells. Pharm Res. 2008 Nov;25(11):2601-12.
5 Involvement of the drug transporters p glycoprotein and multidrug resistance-associated protein Mrp2 in telithromycin transport. Antimicrob Agents Chemother. 2006 Jan;50(1):80-7.
6 Dose-dependent disposition of methotrexate in Abcc2 and Abcc3 gene knockout murine models. Drug Metab Dispos. 2011 Nov;39(11):2155-61.
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8 Enhancing chemosensitivity in oral squamous cell carcinoma by lentivirus vector-mediated RNA interference targeting EGFR and MRP2. Oncol Lett. 2016 Sep;12(3):2107-2114.
9 Multidrug resistance associated protein 2 mediates transport of prostaglandin E2. Liver Int. 2006 Apr;26(3):362-8.
10 Lentivirus-mediated RNAi silencing targeting ABCC2 increasing the sensitivity of a human nasopharyngeal carcinoma cell line against cisplatin. J Transl Med. 2008 Oct 4;6:55.
11 Effect of acetaminophen on expression and activity of rat liver multidrug resistance-associated protein 2 and P-glycoprotein. Biochem Pharmacol. 2004 Aug 15;68(4):791-8.
12 Small intestinal efflux mediated by MRP2 and BCRP shifts sulfasalazine intestinal permeability from high to low, enabling its colonic targeting. Am J Physiol Gastrointest Liver Physiol. 2009 Aug;297(2):G371-7.
13 Delineating the contribution of secretory transporters in the efflux of etoposide using Madin-Darby canine kidney (MDCK) cells overexpressing P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP1), and canalicular multispecific organic anion transporter (cMOAT). Drug Metab Dispos. 2002 Apr;30(4):457-63.
14 Multidrug Resistance-Associated Protein 2 (MRP2) Mediated Transport of Oxaliplatin-Derived Platinum in Membrane Vesicles. PLoS One. 2015 Jul 1;10(7):e0130727.
15 MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents. Cancer Chemother Pharmacol. 2009 Jun;64(1):183-8.
16 Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
17 Folate transporter expression decreases in the human placenta throughout pregnancy and in pre-eclampsia. Pregnancy Hypertens. 2012 Apr;2(2):123-31.
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19 Antiestrogens and steroid hormones: substrates of the human P-glycoprotein. Biochem Pharmacol. 1994 Jul 19;48(2):287-92.
20 Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia. Ther Drug Monit. 2011 Apr;33(2):244-50.
21 Doxorubicin transport by RALBP1 and ABCG2 in lung and breast cancer. Int J Oncol. 2007 Mar;30(3):717-25.
22 Wild-type breast cancer resistance protein (BCRP/ABCG2) is a methotrexate polyglutamate transporter. Cancer Res. 2003 Sep 1;63(17):5538-43.
23 The effect of low pH on breast cancer resistance protein (ABCG2)-mediated transport of methotrexate, 7-hydroxymethotrexate, methotrexate diglutamate, folic acid, mitoxantrone, topotecan, and resveratrol in in vitro drug transport models. Mol Pharmacol. 2007 Jan;71(1):240-9.
24 Role of BCRP as a biomarker for predicting resistance to 5-fluorouracil in breast cancer. Cancer Chemother Pharmacol. 2009 May;63(6):1103-10.
25 Inhibiting the function of ABCB1 and ABCG2 by the EGFR tyrosine kinase inhibitor AG1478. Biochem Pharmacol. 2009 Mar 1;77(5):781-93.
26 Sterol transport by the human breast cancer resistance protein (ABCG2) expressed in Lactococcus lactis. J Biol Chem. 2003 Jun 6;278(23):20645-51.
27 The phytoestrogen genistein enhances multidrug resistance in breast cancer cell lines by translational regulation of ABC transporters. Cancer Lett. 2016 Jun 28;376(1):165-72.
28 Curcumin inhibits the activity of ABCG2/BCRP1, a multidrug resistance-linked ABC drug transporter in mice. Pharm Res. 2009 Feb;26(2):480-7.
29 Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump. Blood. 2004 Nov 1;104(9):2940-2.
30 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
31 Luteolin, an emerging anti-cancer flavonoid, poisons eukaryotic DNA topoisomerase I. Biochem J. 2002 Sep 1;366(Pt 2):653-61.
32 Impact of natural products on developing new anti-cancer agents. Chem Rev. 2009 Jul;109(7):3012-43.
33 Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
34 Characterization of protein kinase chk1 essential for the cell cycle checkpoint after exposure of human head and neck carcinoma A253 cells to a novel topoisomerase I inhibitor BNP1350. Mol Pharmacol.2000 Mar;57(3):453-9.
35 Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer. 2006 Oct;6(10):789-802.
36 Phase I study of topoisomerase I inhibitor exatecan mesylate (DX-8951f) given as weekly 24-hour infusions three of every four weeks. Clin Cancer Res. 2001 Dec;7(12):3963-70.
37 Edotecarin: a novel topoisomerase I inhibitor. Clin Colorectal Cancer. 2005 May;5(1):27-36.
38 Rubitecan. Expert Opin Investig Drugs. 2006 Jan;15(1):71-9.