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. 2025 Jan:141:104673.
doi: 10.1016/j.exphem.2024.104673. Epub 2024 Nov 15.

FT-4202, a selective pyruvate kinase R activator for sickle cell disease

Anna Ericsson  1 , David J Richard  1 , Erik Wilker  1 , David R Lancia Jr  1 , Shawn Fessler  1 , Paul Troccolo  1 , Xiaozhang Zheng  1 , Angela Toms  1 , Christopher Dinsmore  1 , Lili Yao  1 , Frans A Kuypers  2 , Sandra Larkin  2 , Douglas Marcotte  1 , Keertik Fulzele  1 , Maria Ribadeneira  1 , Sylvie M Guichard  3 , Gary Marshall  1
Affiliations
Free article

FT-4202, a selective pyruvate kinase R activator for sickle cell disease

Anna Ericsson et al. Exp Hematol. 2025 Jan.
Free article

Abstract

Anemia in patients with sickle cell disease (SCD) increases 2,3-diphosphoglycerate (2,3-DPG), decreasing hemoglobin-oxygen (HbO2) affinity to improve oxygen offloading and promote hemoglobin polymerization (sickling) of red blood cells (RBCs). We report the discovery of FT-4202, an investigational, selective pyruvate kinase type-R (PKR) activator with a multimodal mechanism of action and potential to increase ATP and decrease 2,3-DPG, resulting in increased HbO2 affinity, decreased Hb polymerization, and improved RBC health. FT-4202 was identified via structure-enabled lead optimization medicinal chemistry using X-ray crystallography, molecular modeling, and thermal shift assays. FT-4202, an allosteric PKR activator, stabilizes the tetrameric enzyme and increases PKR activity in human and mouse RBCs in vitro. Seven-day oral administration of FT-4202 in Berkeley SCD mice reduced 2,3-DPG, increased HbO2 affinity, and reduced RBC sickling versus control. There were no adverse in vitro safety findings. FT-4202 offers a therapeutic opportunity to modify the course of SCD.

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Conflict of interest statement

Conflict of Interest Disclosure This work was funded by Forma Therapeutics, Inc., Watertown, Massachusetts, which was acquired by Novo Nordisk, Watertown, in October 2022. AE, DJR, EW, DRL, SF, PT, XZ, AT, CD, LY, DM, KF, MR, SMG, and GM were employees of Forma Therapeutics, Inc., at the time the work was conducted. FAK and SL were employees of the Children's Hospital Oakland Research Institute. SMG became an employee of Novo Nordisk (following their acquisition of Forma Therapeutics, Inc.) FAK and SL received institutional compensation for the assays performed in the study. AE, DJR, DRL, MR, and GM declare co-invention of multiple patent applications relating to this research project: 1) Applicant: Forma Therapeutics; Inventors: Anna Ericsson, Neal Green, Gary Gustafson, David R. Lancia, Jr., Gary Marshall, Lorna Mitchell, David Richard, Zhongguo Wang, Sanjeev Forsyth, Patrick Kelly, Madhu Mondal, Maria Ribadeneira, Patricia Schroeder; Application number: US-2020129485-A1; Status: Pending; Specific aspect of manuscript covered in patent application: Discovery and use of FT-4202 to treat sickle cell disease. 2) Applicant: Forma Therapeutics; Inventor(s): Anna Ericsson, Neal Green, Gary Gustafson, David R. Lancia, Jr., Gary Marshall, Lorna Mitchell, David Richard, Zhongguo Wang; Patent number: US 10,675,274 B2; Status: Awarded; Specific aspect of manuscript covered in patent application: Compound synthesis, biochemical, and cellular activities of compounds. 3) Applicant: Forma Therapeutics; Inventor(s): David R. Lancia, Gary Gustafson, Neal Green, Lorna Mitchell, Anna Ericsson, David Richard; Patent Number: US 11,001,588 B2; Status: Awarded; Specific aspect of manuscript covered in patent application: Compound synthesis and biochemical activities of compounds. 4) Applicant: Forma Therapeutics; Inventor(s): Anna Ericsson, Neal Green, Gary Gustafson, Bingsong Han, David R. Lancia, Jr., Lorna Mitchell, David Richard, Tatiana Shelekhin, Chase C. Smith, Zhongguo Wang, Xiaozhang Zheng; Patent number: US 11,014,927 B2; Status: Awarded; Specific aspect of manuscript covered in patent application: Compound synthesis, biochemical, and cellular activities of compounds. 5) Applicant: Forma Therapeutics; Inventor(s): Anna Ericsson, Neal Green, Gary Gustafson, David R. Lancia, Jr., Gary Marshall, Lorna Mitchell, David Richard, Zhongguo Wang; Patent number: US 11,071,725 B2; Status: Awarded; Specific aspect of manuscript covered in patent application: Compound synthesis, biochemical, and cellular activities of compounds. AE, EW, SF, PT, XZ, AT, CD, LY, DM, MR, and GM have no additional financial or non-financial competing interests to declare.

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