Tandutinib

Identification

Name
Tandutinib
Accession Number
DB05465
Type
Small Molecule
Groups
Investigational
Description

MLN518 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
Not Available
External IDs
CT-53518 / CT53518 / MLN-518
International/Other Brands
Tandutinib
Categories
UNII
E1IO3ICJ9A
CAS number
387867-13-2
Weight
Average: 562.703
Monoisotopic: 562.326753862
Chemical Formula
C31H42N6O4
InChI Key
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

Pharmacology

Indication

Investigated for use/treatment in leukemia (myeloid).

Structured Indications
Not Available
Pharmacodynamics

MLN518 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 action

MLN518 inhibits tyrosine kinases; Specifically, it is selective for FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR).

TargetActionsOrganism
UReceptor-type tyrosine-protein kinase FLT3Not AvailableHuman
UPlatelet-derived growth factor DNot AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
VemurafenibThe risk or severity of QTc prolongation can be increased when Vemurafenib is combined with Tandutinib.Approved
Food Interactions
Not Available

References

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
PubChem Compound
3038522
PubChem Substance
175427013
ChemSpider
2302085
BindingDB
13535
ChEBI
90237
ChEMBL
CHEMBL124660

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAcute Myelogenous Leukaemia (AML) / Myelodysplastic Syndrome1
1WithdrawnTreatmentGlioblastoma Multiforme1
1, 2CompletedTreatmentAdult Brain Tumors / Adult Giant Cell Glioblastoma / Adult Glioblastoma / Adult Gliosarcoma / Recurrent Adult Brain Tumor1
1, 2WithdrawnNot AvailableAcute Myelogenous Leukaemia (AML)1
2CompletedTreatmentAnaplastic Astrocytoma (AA) / Anaplastic Mixed Oligoastrocytoma / Anaplastic Oligodendroglioma (AO) / Glioblastomas / Gliosarcoma1
2CompletedTreatmentClear Cell Renal Cell Carcinoma / Recurrent Renal Cell Cancer / Stage IV Renal Cell Cancer1
2CompletedTreatmentMetastatic Cancers / Pain / Prostate Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not 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 FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazinanes
Sub Class
Piperazines
Direct Parent
N-arylpiperazines
Alternative Parents
Quinazolinamines / N-phenylureas / Piperazine carboxamides / Phenoxy compounds / Dialkylarylamines / Anisoles / Alkyl aryl ethers / Aminopyrimidines and derivatives / Piperidines / Imidolactams
show 8 more
Substituents
N-arylpiperazine / Quinazolinamine / N-phenylurea / Diazanaphthalene / Quinazoline / Piperazine-1-carboxamide / Phenoxy compound / Anisole / Dialkylarylamine / Phenol ether
show 24 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not 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...
Gene Name
FLT3
Uniprot ID
P36888
Uniprot Name
Receptor-type tyrosine-protein kinase FLT3
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. P...
Gene Name
PDGFD
Uniprot ID
Q9GZP0
Uniprot Name
Platelet-derived growth factor D
Molecular Weight
42847.865 Da

Drug created on November 18, 2007 11:25 / Updated on December 01, 2017 15:36