AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency

  • Blood. 2017 Sep 14;130(11):1347-1356. doi: 10.1182/blood-2016-11-753525.
Charles Kung  1 ,  Jeff Hixon  1 ,  Penelope A Kosinski  1 ,  Giovanni Cianchetta  1 ,  Gavin Histen  1 ,  Yue Chen  1 ,  Collin Hill  1 ,  Stefan Gross  1 ,  Yaguang Si  1 ,  Kendall Johnson  1 ,  Byron DeLaBarre  1 ,  Zhiyong Luo  2 ,  Zhiwei Gu  2 ,  Gui Yao  2 ,  Huachun Tang  2 ,  Cheng Fang  2 ,  Yingxia Xu  2 ,  Xiaobing Lv  2 ,  Scott Biller  1 ,  Shin-San Michael Su  1 ,  Hua Yang  1 ,  Janeta Popovici-Muller  1 ,  Francesco Salituro  1 ,  Lee Silverman  1 ,  Lenny Dang  1
Affiliations
  • 1. Agios Pharmaceuticals, Inc., Cambridge, MA; and.
  • 2. Shanghai ChemPartner Co., Ltd., Shanghai, China.
PMID: 28760888 DOI: 10.1182/blood-2016-11-753525
Abstract

Pyruvate Kinase (PK) deficiency is a rare genetic disease that causes chronic hemolytic anemia. There are currently no targeted therapies for PK deficiency. Here, we describe the identification and characterization of AG-348, an allosteric activator of PK that is currently in clinical trials for the treatment of PK deficiency. We demonstrate that AG-348 can increase the activity of wild-type and mutant PK Enzymes in biochemical assays and in patient red blood cells treated ex vivo. These data illustrate the potential for AG-348 to restore the glycolytic pathway activity in patients with PK deficiency and ultimately lead to clinical benefit.

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