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

Charles Kung, Jeff Hixon, Penelope A Kosinski, Giovanni Cianchetta, Gavin Histen, Yue Chen, Collin Hill, Stefan Gross, Yaguang Si, Kendall Johnson, Byron DeLaBarre, Zhiyong Luo, Zhiwei Gu, Gui Yao, Huachun Tang, Cheng Fang, Yingxia Xu, Xiaobing Lv, Scott Biller, Shin-San Michael Su, Hua Yang, Janeta Popovici-Muller, Francesco Salituro, Lee Silverman and Lenny Dang

Key points

  • AG-348 is a small molecule allosteric activator of WT red cell pyruvate kinase as well as mutant enzymes associated with hemolytic anemia

  • Activity in vitro, in mice, and in red blood cells suggests it may address the underlying molecular pathology in PK deficiency patients

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.

  • Submitted November 28, 2016.
  • Accepted July 3, 2017.