Details of the Drug

General Information of Drug (ID: DMAYTRK)

• Drug Name: H3B-6527
• Synonyms: MBWRLLRCTIYXDW-UHFFFAOYSA-N; 1702259-66-2; UNII-4HTE364XIK; 4HTE364XIK; N-[2-[[6-[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl-methylamino]pyrimidin-4-yl]amino]-5-(4-ethylpiperazin-1-yl)phenyl]prop-2-enamide; Eisai/H3 Biomedicine; CHEMBL3939295; SCHEMBL16659467; BDBM249396; EX-A1510; BCP17555; ZINC521836463; AKOS032960479; H3B6527; CS-5830; ACN-037543; AK684091; AC-29878; HY-100491; US9434697, 108; N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)acryla

Indication

Disease Entry	ICD 11	Status	REF
Hepatocellular carcinoma	2C12.02	Phase 1	[1]

• #Ro5 Violations (Lipinski): 1:
  Molecular Weight (mw); 629.5
  Topological Polar Surface Area (xlogp); 4.4
  Rotatable Bond Count (rotbonds); 10
  Hydrogen Bond Donor Count (hbonddonor); 3
  Hydrogen Bond Acceptor Count (hbondacc); 9
• Chemical Identifiers:
  Formula: C29H34Cl2N8O4
  IUPAC Name: N-[2-[[6-[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl-methylamino]pyrimidin-4-yl]amino]-5-(4-ethylpiperazin-1-yl)phenyl]prop-2-enamide
  Canonical SMILES: CCN1CCN(CC1)C2=CC(=C(C=C2)NC3=CC(=NC=N3)N(C)C(=O)NC4=C(C(=CC(=C4Cl)OC)OC)Cl)NC(=O)C=C
  InChI: InChI=1S/C29H34Cl2N8O4/c1-6-25(40)35-20-14-18(39-12-10-38(7-2)11-13-39)8-9-19(20)34-23-16-24(33-17-32-23)37(3)29(41)36-28-26(30)21(42-4)15-22(43-5)27(28)31/h6,8-9,14-17H,1,7,10-13H2,2-5H3,(H,35,40)(H,36,41)(H,32,33,34)
  InChIKey: MBWRLLRCTIYXDW-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 118029202
  CAS Number: 1702259-66-2
  DrugBank ID: DB15169
  TTD ID: D0D6XT
  INTEDE ID: DR1800

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
FGFR4 messenger RNA (FGFR4 mRNA)	TT1KX2S	FGFR4_HUMAN	Inhibitor	[1]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[2]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Substrate	[2]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] Correlation of the in vitro biotransformation of H3B-6527 in dog and human hepatocytes with the in vivo metabolic profile of 14C-H3B-6527 in a dog mass balance study. Xenobiotica. 2020 Apr;50(4):458-467.
• [3] 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.
• [4] Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
• [5] 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.
• [6] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [7] 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.
• [8] 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.
• [9] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Drug Interactions Flockhart Table
• [16] 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.
• [17] Urinary 6 beta-hydroxycortisol excretion in rheumatoid arthritis. Br J Rheumatol. 1997 Jan;36(1):54-8.
• [18] Clinical pharmacokinetics of imatinib. Clin Pharmacokinet. 2005;44(9):879-94.
• [19] Kinetics and regulation of cytochrome P450-mediated etoposide metabolism. Drug Metab Dispos. 2004 Sep;32(9):993-1000.
• [20] Differential mechanism-based inhibition of CYP3A4 and CYP3A5 by verapamil. Drug Metab Dispos. 2005 May;33(5):664-71.
• [21] Clinical pipeline report, company report or official report of ISIS Pharmaceuticals (2011).
• [22] Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases. J Med Chem. 2000 Nov 30;43(24):4606-16.
• [23] Biological evaluation of a multi-targeted small molecule inhibitor of tumor-induced angiogenesis. Bioorg Med Chem Lett. 2006 Apr 1;16(7):1950-3.