The search for pyruvate kinase-R activators; from a HTS screening hit via an impurity to the discovery of a lead series.
Bioorg Med Chem Lett
; 110: 129865, 2024 Sep 15.
Article
in En
| MEDLINE
| ID: mdl-38950758
ABSTRACT
Pyruvate kinase (PK) is an essential component of cellular metabolism, converting ADP and phosphoenolpyruvate (PEP) to pyruvate in the final step of glycolysis. Of the four unique isoforms of pyruvate kinase, R (PKR) is expressed exclusively in red blood cells and is a tetrameric enzyme that depends on fructose-1,6-bisphosphate (FBP) for activation. PKR deficiency leads to hemolysis of red blood cells resulting in anemia. Activation of PKR in both sickle cell disease and beta-thalassemia patients could lead to improved red blood cell fitness and survival. The discovery of a novel series of substituted urea PKR activators, via the serendipitous identification and diligent characterization of a minor impurity in an High Throughput Screening (HTS) hit will be discussed.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyruvate Kinase
/
High-Throughput Screening Assays
Limits:
Animals
/
Humans
Language:
En
Journal:
Bioorg Med Chem Lett
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
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