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Identification
NameMLN-518
Accession NumberDB05465
TypeSmall Molecule
GroupsInvestigational
DescriptionMLN518 is a novel, oral, small molecule designed to inhibit type III receptor tyrosine kinases, including FLT3, (platelet-derived growth-factor receptor) PDGFR and c-KIT. Tyrosine kinases are enzymes involved in several cellular processes and are known to be activated in cancer cells to drive tumor growth. AML patients with FLT3 mutations experience earlier disease relapse and shorter survival rates compared to patients without these mutations. Approximately 25 to 30 percent of all adult AML patients have a mutation of the FLT3 gene. The use of MLN518 to treat AML has been granted fast-track status by the U.S. Food and Drug Administration. Phase I/II trials are underway.
Structure
Thumb
Synonyms
tandutinib
External Identifiers
  • CT53518
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
TandutinibNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIE1IO3ICJ9A
CAS numberNot Available
WeightAverage: 562.703
Monoisotopic: 562.326753862
Chemical FormulaC31H42N6O4
InChI KeyInChIKey=UXXQOJXBIDBUAC-UHFFFAOYSA-N
InChI
InChI=1S/C31H42N6O4/c1-23(2)41-25-10-8-24(9-11-25)34-31(38)37-17-15-36(16-18-37)30-26-20-28(39-3)29(21-27(26)32-22-33-30)40-19-7-14-35-12-5-4-6-13-35/h8-11,20-23H,4-7,12-19H2,1-3H3,(H,34,38)
IUPAC Name
4-{6-methoxy-7-[3-(piperidin-1-yl)propoxy]quinazolin-4-yl}-N-[4-(propan-2-yloxy)phenyl]piperazine-1-carboxamide
SMILES
COC1=C(OCCCN2CCCCC2)C=C2N=CN=C(N3CCN(CC3)C(=O)NC3=CC=C(OC(C)C)C=C3)C2=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as n-arylpiperazines. These are organic compounds containing a piperazine ring where the nitrogen ring atom carries an aryl group.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassDiazinanes
Sub ClassPiperazines
Direct ParentN-arylpiperazines
Alternative Parents
Substituents
  • N-arylpiperazine
  • Quinazolinamine
  • Quinazoline
  • N-phenylurea
  • Piperazine-1-carboxamide
  • Dialkylarylamine
  • Phenol ether
  • Anisole
  • Aminopyrimidine
  • Alkyl aryl ether
  • Imidolactam
  • Benzenoid
  • Pyrimidine
  • Piperidine
  • Monocyclic benzene moiety
  • Heteroaromatic compound
  • Urea
  • Tertiary aliphatic amine
  • Tertiary amine
  • Azacycle
  • Ether
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationInvestigated for use/treatment in leukemia (myeloid).
PharmacodynamicsMLN518 is a novel quinazoline-based small molecule inhibitor of the FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases with that has been shown to have great efficacy in murine models of FLT3 ITD-positive leukemia. Experiments with mice demonstrate that at effective concentrations, MLN518 has mild toxicity toward normal hematopoiesis for FLT3 ITD-positive leukemia. MLN518 has also been shown to preferentially inhibit the growth of blast colonies from FLT3 ITD-positive as compared to ITD-negative patients with AML, without significantly affecting colony formation by normal human progenitor cells.
Mechanism of actionMLN518 inhibits tyrosine kinases; Specifically, it is selective for FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR).
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organismsNot Available
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9955
Blood Brain Barrier+0.9533
Caco-2 permeable+0.5086
P-glycoprotein substrateSubstrate0.7822
P-glycoprotein inhibitor IInhibitor0.7745
P-glycoprotein inhibitor IIInhibitor0.5673
Renal organic cation transporterNon-inhibitor0.6446
CYP450 2C9 substrateNon-substrate0.7887
CYP450 2D6 substrateNon-substrate0.7857
CYP450 3A4 substrateSubstrate0.8103
CYP450 1A2 substrateNon-inhibitor0.7872
CYP450 2C9 inhibitorInhibitor0.6167
CYP450 2D6 inhibitorNon-inhibitor0.8805
CYP450 2C19 inhibitorNon-inhibitor0.7293
CYP450 3A4 inhibitorNon-inhibitor0.7285
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7373
Ames testNon AMES toxic0.6764
CarcinogenicityNon-carcinogens0.8818
BiodegradationNot ready biodegradable0.996
Rat acute toxicity2.2288 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6936
hERG inhibition (predictor II)Inhibitor0.8758
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0753 mg/mLALOGPS
logP4.52ALOGPS
logP4.34ChemAxon
logS-3.9ALOGPS
pKa (Strongest Acidic)14.01ChemAxon
pKa (Strongest Basic)9.03ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area92.29 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity162.58 m3·mol-1ChemAxon
Polarizability64.11 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis ReferenceNot Available
General References
  1. DeAngelo DJ, Stone RM, Heaney ML, Nimer SD, Paquette RL, Klisovic RB, Caligiuri MA, Cooper MR, Lecerf JM, Karol MD, Sheng S, Holford N, Curtin PT, Druker BJ, Heinrich MC: Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood. 2006 Dec 1;108(12):3674-81. Epub 2006 Aug 10. [PubMed:16902153 ]
  2. Kiyoi H: [The present status of, and problems with the development of FLT3 kinase inhibitors]. Rinsho Ketsueki. 2006 Apr;47(4):270-7. [PubMed:16715961 ]
  3. Kiyoi H: [Possibility of targeting FLT3 kinase for the treatment of leukemia]. Rinsho Ketsueki. 2005 Mar;46(3):187-97. [PubMed:16447713 ]
  4. Griswold IJ, Shen LJ, La Rosee P, Demehri S, Heinrich MC, Braziel RM, McGreevey L, Haley AD, Giese N, Druker BJ, Deininger MW: Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis. Blood. 2004 Nov 1;104(9):2912-8. Epub 2004 Jul 8. [PubMed:15242881 ]
  5. Brownlow N, Vaid M, Dibb NJ: Tandutinib inhibits FMS receptor signalling, and macrophage and osteoclast formation in vitro. Leukemia. 2008 Jul;22(7):1452-3. doi: 10.1038/sj.leu.2405085. Epub 2008 Jan 10. [PubMed:18185521 ]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Vascular endothelial growth factor-activated receptor activity
Specific Function:
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or...
Gene Name:
FLT3
Uniprot ID:
P36888
Molecular Weight:
112902.51 Da
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Not Available
Specific Function:
Growth factor that plays an essential role in the regulation of embryonic development, cell proliferation, cell migration, survival and chemotaxis. Potent mitogen for cells of mesenchymal origin. Plays an important role in wound healing. Induces macrophage recruitment, increased interstitial pressure, and blood vessel maturation during angiogenesis. Can initiate events that lead to a mesangial ...
Gene Name:
PDGFD
Uniprot ID:
Q9GZP0
Molecular Weight:
42847.865 Da
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Drug created on November 18, 2007 11:25 / Updated on August 17, 2016 12:24