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Characterization of Sickling During Controlled Automated Deoxygenation with Oxygen Gradient Ektacytometry

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

Anna Ericsson¹, David J Richard¹, Erik Wilker¹

¹Forma Therapeutics, Inc., Watertown, MA.

Experimental Hematology

|November 16, 2024

Summary

FT-4202, a novel pyruvate kinase-R activator, shows promise for sickle cell disease (SCD). It reduces red blood cell sickling by increasing oxygen affinity and improving cellular health.

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A Precision Medicine Tool for Measurement and Monitoring of Hemoglobin S in Sickle Cell Disease Patients Receiving Transfusion Therapy

A Precision Medicine Tool for Measurement and Monitoring of Hemoglobin S in Sickle Cell Disease Patients Receiving Transfusion Therapy

Area of Science:

Biochemistry
Hematology
Pharmacology

Background:

Sickle cell disease (SCD) involves anemia, reduced hemoglobin-oxygen (HbO2) affinity, and red blood cell (RBC) sickling.
Elevated 2,3-diphosphoglycerate (2,3-DPG) in SCD exacerbates these conditions by decreasing HbO2 affinity.

Purpose of the Study:

To discover and characterize FT-4202, a selective pyruvate kinase-R (PKR) activator.
To evaluate FT-4202's potential to improve RBC health and modify SCD pathophysiology.

Main Methods:

Structure-enabled medicinal chemistry, including X-ray crystallography, molecular modeling, and thermal shift assays.
In vitro studies of PKR activation in human and mouse RBCs.
In vivo efficacy study of FT-4202 in a mouse model of SCD.

Main Results:

FT-4202 demonstrated allosteric activation of PKR, increasing enzyme activity and stabilizing its tetrameric form.
In vitro, FT-4202 increased ATP levels and decreased 2,3-DPG in RBCs.
Oral administration of FT-4202 in SCD mice reduced 2,3-DPG, increased HbO2 affinity, and decreased RBC sickling.

Conclusions:

FT-4202 is a potent PKR activator with a multimodal mechanism of action.
FT-4202 has the potential to increase HbO2 affinity, decrease Hb polymerization, and improve RBC health in SCD.
FT-4202 represents a promising therapeutic candidate for modifying the course of sickle cell disease.