MLN-518

Synonyms :
tandutinib

Status : 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.

Used

Investigated for use/treatment in leukemia (myeloid).

Mechanism Of Action

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

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.

Chemical Classification

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.

N-arylpiperazines

Organic compounds

Organoheterocyclic compounds

Diazinanes

Piperazines

Chemical Name

tandutinib

Calculated Property

kind Value Source
logP 4.52 ALOGPS
logS -3.9 ALOGPS
Water Solubility 7.53e-02 g/l ALOGPS
logP 4.34 ChemAxon
IUPAC Name 4-{6-methoxy-7-[3-(piperidin-1-yl)propoxy]quinazolin-4-yl}-N-[4-(propan-2-yloxy)phenyl]piperazine-1-carboxamide ChemAxon
Traditional IUPAC Name tandutinib ChemAxon
Molecular Weight 562.703 ChemAxon
Monoisotopic Weight 562.326753862 ChemAxon
SMILES COC1=C(OCCCN2CCCCC2)C=C2N=CN=C(N3CCN(CC3)C(=O)NC3=CC=C(OC(C)C)C=C3)C2=C1 ChemAxon
Molecular Formula C31H42N6O4 ChemAxon
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) ChemAxon
InChIKey InChIKey=UXXQOJXBIDBUAC-UHFFFAOYSA-N ChemAxon
Polar Surface Area (PSA) 92.29 ChemAxon
Refractivity 162.58 ChemAxon
Polarizability 64.11 ChemAxon
Rotatable Bond Count 10 ChemAxon
H Bond Acceptor Count 8 ChemAxon
H Bond Donor Count 1 ChemAxon
pKa (strongest acidic) 14.01 ChemAxon
pKa (strongest basic) 9.03 ChemAxon
Physiological Charge 1 ChemAxon
Number of Rings 5 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five 0 ChemAxon
Ghose Filter 0 ChemAxon
MDDR-Like Rule 1 ChemAxon

Target within organism

  • Receptor-type tyrosine-protein kinase FLT3 : in Human
  • Platelet-derived growth factor D : in Human