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ML001 : bPK (B. stearothermophilus Pyruvate Kinase) Inhibitor

ML001

ML001

Target Name

B. stearothermophilus Pyruvate Kinase

Target Alias

bPK

Target Class

Kinase

Mechanism of Action

Inhibitor of bPK

Biological / Disease Relevance

Bacterial anti-infectives

In vitro assay
IC50
0.25 uM
In vitro assay
Ki
0.20 uM
Inactive Control
Available

Target Information

Pyruvate kinase (PK) is a critical metabolic enzyme operating in the ultimate step in glycolysis where it catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to ADP, yielding one molecule of pyruvate and one molecule of ATP. PK from bacillus stearothermophilus (bPK) is an allosteric enzyme activated by monophosphate sugars such as AMP or ribose 5-phosphate and therefore shows different allosteric regulation than human isozymes that are regulated by the bis-phosphorylated sugar, fructose1,6-bisphosphate. Inhibitors of bPK have been identified through a proof-of-principle qHTS assay. This scaffold is currently being examined as means to understand and design chemical series that are capable of inhibiting the PKs from bacillus and other bacterial species.

Properties

ML001

MLS000042013

Physical & chemical properties
Molecular Weight 353.8 g/mol
Molecular Formula C19H16ClN3O2
cLogP 4.8
PSA 62.3
Storage -20
Solubility Up to 10mM in DMSO
CAS Number

SMILES:
N#CC1=C(OC(C2=CC=C(C=C2)OCC3=CC=C(C=C3)Cl)=N1)N(C)C

InChI:
InChI=1S/C19H16ClN3O2/c1-23(2)19-17(11-21)22-18(25-19)14-5-9-16(10-6-14)24-12-13-3-7-15(20)8-4-13/h3-10H,12H2,1-2H3

InChIKey:
CMVJGSUPZYIDHO-UHFFFAOYSA-N

Activity

Summary activity statement /

ML001 (SID 862236 ; CID 663459) is observed to be a  potent and selective inhibitor of Bacillus stearothermophilus Pyruvate Kinase. ML001 is a compound belonging to class Pyruvinb; type Bacruvinb. This probe has been tested in > 800 bioassays found within PubChem and was designated as active in 16 assays. ML001 exhibited potency against the bacterial PK with a 250 nM IC50 inhibition; while showing > 5 uM AC50 against the rest. This compound may show fluorescence which would explain the activity in spectroscopic profiling assay. The inactivity in > 700 PubChem assay would suggest that this is a highly selective compound. ML001 acts as a mixed-type inhibitor with respect to ADP and showed a Ki of 200 nM.

In vitro activity

bPK-Luciferase (IC50) humanPK Luciferase Counterscreen Luciferase Assay Counterscreen

MLS000042013 (ML001)

 0.25 uM >=240 uM (Inactive @ 60uM) Inactive

NCGC00053176 (inactive analog)

 Inactive Not Tested Inactive

References

  1. Engineering of Bacillus subtilis for Enhanced Total Synthesis of Folic Acid.
  2. Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries.
  3. The scaffold tree--visualization of the scaffold universe by hierarchical scaffold classification.