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

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. 2024 Jun 29:110:129865. doi: 10.1016/j.bmcl.2024.129865.
Chul Yu 1,  Lina Quattrocchio Setti 2,  Shahul Nilar 3,  Zhe Li 4,  Ming Yu 5,  James Partridge 6,  Rebeca Choy 7,  Vincent Siu 8,  Steven Strutt 9,  Richard Zang 7,  Peter Rademacher 10,  Soheila Bahmanjah 3,  Yekaterina Myslovaty 11,  Manuel Zancanella 4
Affiliations

Affiliations

  • 1 Global Blood Therapeutics/Pfizer Inc., 181 Oyster Point Blvd, South San Francisco, CA 94080, United States; Pharmaron, 6 Venture, Suite 250, Irvine, CA, 92618, United States.
  • 2 Global Blood Therapeutics/Pfizer Inc., 181 Oyster Point Blvd, South San Francisco, CA 94080, United States. Electronic address: lina.quattrocchio@gmail.com.
  • 3 Global Blood Therapeutics/Pfizer Inc., 181 Oyster Point Blvd, South San Francisco, CA 94080, United States.
  • 4 Global Blood Therapeutics/Pfizer Inc., 181 Oyster Point Blvd, South San Francisco, CA 94080, United States; Gate Bioscience, 2000 Sierra Point Parkway, Suite 200, Brisbane, CA 94005, United States.
  • 5 Global Blood Therapeutics/Pfizer Inc., 181 Oyster Point Blvd, South San Francisco, CA 94080, United States; Allorion Therapeutics, 22 Strathmore Road, Natik, MA 01760, United States.
  • 6 Global Blood Therapeutics/Pfizer Inc., 181 Oyster Point Blvd, South San Francisco, CA 94080, United States; Novartis Institutes for Biomedical Research, 5959 Horton St, Emeryville, CA 94608, United States.
  • 7 Global Blood Therapeutics/Pfizer Inc., 181 Oyster Point Blvd, South San Francisco, CA 94080, United States; IDEAYA Biosciences, 7000 Shoreline Ct #350, South San Francisco, CA 94080, United States.
  • 8 Global Blood Therapeutics/Pfizer Inc., 181 Oyster Point Blvd, South San Francisco, CA 94080, United States; Lenz Therapeutics, 445 Marine View Ave Suite 320, Del Mar, CA 92014, United States.
  • 9 Global Blood Therapeutics/Pfizer Inc., 181 Oyster Point Blvd, South San Francisco, CA 94080, United States; Evercrisp Biosciences, 2630 Bancroft Way, Berkeley, CA 94704, United States.
  • 10 Global Blood Therapeutics/Pfizer Inc., 181 Oyster Point Blvd, South San Francisco, CA 94080, United States; Septerna, 250 East Grand Avenue, South San Francisco, CA 94080, United States.
  • 11 Global Blood Therapeutics/Pfizer Inc., 181 Oyster Point Blvd, South San Francisco, CA 94080, United States; Dice Therapeutics, Subsidiary of Eli-Lilly, 400 E Jamie CT, Third Floor, South San Francisco, CA 94080, United States.
PMID: 38950758 DOI: 10.1016/j.bmcl.2024.129865
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.

Keywords

High throughput screen; Non-malignant hematology; Pyruvate kinase; Urea.

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