The search for pyruvate kinase-R activators; from a HTS screening hit via an impurity to the discovery of a lead series

• Published in: Bioorganic & medicinal chemistry letters Vol. 110; pp. 129865 - 129869
• Main Authors: Yu, Chul, Setti, Lina Quattrocchio, Nilar, Shahul, Li, Zhe, Yu, Ming, Partridge, James, Choy, Rebeca, Siu, Vincent, Strutt, Steven, Zang, Richard, Rademacher, Peter, Bahmanjah, Soheila, Myslovaty, Yekaterina, Zancanella, Manuel
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.09.2024; Elsevier
• Subjects: Chemistry; Chemistry, Medicinal; Chemistry, Organic; High throughput screen; Life Sciences & Biomedicine; Non-malignant hematology; Pharmacology & Pharmacy; Physical Sciences; Pyruvate kinase; Science & Technology; Urea; Urea; High throughput screen; Non-malignant hematology; Pyruvate kinase
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2024.129865

[Display omitted] •High throughput screen provided a developable lead for Pyruvate Kinase activator small molecule.•SAR expansion around the lead did not provide any improvement in potency and activation.•Analytical revision of the initial hit revealed the presence of an active impurity.•Identification, re-synthesis and characterization of the impurity provided a new lead.•SAR around the new lead led to a suitable tool molecule. 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.