ML083 : PKM (Pyruvate Kinase M2) Activator
ML083
Target Name
Pyruvate Kinase M2
Target Alias
PKM
Target Class
Kinase
Mechanism of Action
Activator of PKM
Biological / Disease Relevance
Tumor cell growth and proliferation, Glucose metabolism
In vitro activity
hPK-M2 AC50In vitro activity
hPK-M1 AC50In vitro activity
X-ray CrystallographyTarget Information
Expression of hPK-M2 in cancer cells appears critical for tumor cell growth and proliferation in vivo. In addition, the ability of PK-M2 to be regulated by both FBP and tyrosine phosphorylated proteins is necessary for cancer cell proliferation. Because PK-M2 is the sole pyruvate kinase isoform expressed in all cancer cells studied, it represents a target for drug development that would enable the inhibition of glucose metabolism in a relatively tumor-specific manner.
Project Team
Properties
ML083
NCGC00030335
| Physical & chemical properties | ||||
|---|---|---|---|---|
| Molecular Weight | 454.5 g/mol | |||
| Molecular Formula | C19H22N2O7S2 | |||
| cLogP | 1.4 | |||
| PSA | 119 | |||
| Storage | ||||
| Solubility | soluble at 10 mM in DMSO | |||
| CAS Number | ||||
SMILES:
COC1=CC=C(S(=O)(N2CCN(S(=O)(C3=CC4=C(OCCO4)C=C3)=O)CC2)=O)C=C1
InChI:
InChI=1S/C19H22N2O7S2/c1-26-15-2-4-16(5-3-15)29(22,23)20-8-10-21(11-9-20)30(24,25)17-6-7-18-19(14-17)28-13-12-27-18/h2-7,14H,8-13H2,1H3
InChIKey:
HMGDKYUJSFVHIY-UHFFFAOYSA-N
Activity
Summary activity statement /
ML083 (CID 650361; SID 847943; SID 57646205) is a member of a series of highly specific allosteric activators for the tumor-specific isoform of human pyruvate kinase (M2 isoform). The activation occurs in a manner that is kinetically similar to the natural activator (FBP) by decreasing the Km for PEP and reducing the cooperative binding of PEP.
| ML083 | |
|---|---|
|
hPK-M2 |
0.6 uM |
|
hPK-R |
30% activation at 57 uM |
|
hPK-L |
Inactive |
|
hPK-M1 |
Inactive |
Summary /
ML083 is observed to selectively target the hPK-M2 with a low micromolar potency. It has a greater than 30 fold selectivity against the human muscle pyruvate kinase isoform 2 (hPK-M2) than compared to human reticulocyte PK (hPK-R); and greater than 100 fold compared to human liver PK (hPK-L) and human muscle PK isoform 1 (hPK-M1).
In vitro activity - Mode of action
Summary /
ML083 ( affect the cooperativity of PEP binding with little affect on ADP binding in a manner similar to FBP (a known hPK activator) but with lower efficacy.
Figure 1. Kinetics of substrate binding in the presence (open circles) or absence (filled squares) of activator (10 μM was used). Vo, initial rate in pmol/min as determined in the PK-LDH coupled assay.
In vitro activity - X-ray Crystallography
Summary /
Preliminary X-ray data obtained for co-crystals of ML083 bound to human PK M2 (PDB 3GQY) suggests this occurs by binding at interface that spans the dimer-dimer interaction region of the tetramer, which we infer stabilizes the high affinity R-state of the tetramer.