ML082 : PKM (Pyruvate Kinase M2) Activator
ML082
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 AC50Target 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
ML082
NCGC00031955
| Physical & chemical properties | ||||
|---|---|---|---|---|
| Molecular Weight | 327.38 g/mol | |||
| Molecular Formula | C17H14FN3OS | |||
| cLogP | 3.1 | |||
| PSA | 37.6 | |||
| Storage | ||||
| Solubility | soluble at 10mM in DMSO | |||
| CAS Number | ||||
SMILES:
CC1=CC2=C(S1)C(C=NN(C3=O)CC4=C(F)C=CC=C4)=C3N2C
InChI:
InChI=1S/C17H14FN3OS/c1-10-7-14-16(23-10)12-8-19-21(17(22)15(12)20(14)2)9-11-5-3-4-6-13(11)18/h3-8H,9H2,1-2H3
InChIKey:
IEWYEWDDQWYJLU-UHFFFAOYSA-N
Activity
Summary activity statement /
ML082 (CID 654376; SID 851783) 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.
In vitro activity - Selectivity Assay
| ML082 AC50 | |
|---|---|
|
hPK-M2 |
0.2 uM |
|
hPK-L |
4 uM |
|
hPK-R |
4 uM |
|
hPK-M1 |
Inactive |
Summary /
ML082 is observed to selectively target the hPK-M2 with a low micromolar potency. It has a greater than 10 fold selectivity against the human muscle pyruvate kinase isoform 2 (hPK-M2) than compared to human liver PK (hPK-L) and human reticulocyte PK (hPK-R); and greater than 100 fold compared to human muscle PK isoform 1 (hPK-M1).
In vitro activity - Mode of action
Summary /
ML082 (CID654376) 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.