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

被引：87

作者：

Kung, Charles ^{[1
]}

Hixon, Jeff ^{[1
]}

Kosinski, Penelope A. ^{[1
]}

Cianchetta, Giovanni ^{[1
]}

Histen, Gavin ^{[1
]}

Chen, Yue ^{[1
]}

Hill, Collin ^{[1
]}

Gross, Stefan ^{[1
]}

Si, Yaguang ^{[1
]}

Johnson, Kendall ^{[1
]}

DeLaBarre, Byron ^{[1
]}

Luo, Zhiyong ^{[2
]}

Gu, Zhiwei ^{[2
]}

Yao, Gui ^{[2
]}

Tang, Huachun ^{[2
]}

Fang, Cheng ^{[2
]}

Xu, Yingxia ^{[2
]}

Lv, Xiaobing ^{[2
]}

Biller, Scott ^{[1
]}

Su, Shin-San Michael ^{[1
]}

Yang, Hua ^{[1
]}

Popovici-Muller, Janeta ^{[1
]}

Salituro, Francesco ^{[1
]}

Silverman, Lee ^{[1
]}

Dang, Lenny ^{[1
]}

机构：

[1] Agios Pharmaceut Inc, Cambridge, MA USA

[2] Shanghai ChemPartner Co Ltd, Shanghai, Peoples R China

来源：

BLOOD | 2017年 / 130卷 / 11期

关键词：

NONSPHEROCYTIC HEMOLYTIC-ANEMIA; PK-LR GENE; RIBOFLAVIN TREATMENT; STEM-CELLS; ERYTHROCYTE; GENERATION; CANCER; ENZYME; MUTANT;

D O I：

10.1182/blood-2016-11-753525

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：1347 / 1356

页数：10

共 18 条

[1] Red cell pyruvate kinase deficiency in Southern Sardinia
Perseu, L.
Giagu, N.
Satta, S.
Sollaino, M. C.
Congiu, R.
Galanello, R.
BLOOD CELLS MOLECULES AND DISEASES, 2010, 45 (04) : 280 - 283
[2] AG-348 (mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and adenosine triphosphate levels over a broad range of PKLR genotypes
Rab, Minke A. E.
van Oirschot, Brigitte A.
Kosinski, Penelope A.
Hixon, Jeffrey
Johnson, Kendall
Chubukov, Victor
Dang, Lenny
Pasterkamp, Gerard
van Straaten, Stephanie
van Solinge, Wouter W.
van Beers, Eduard J.
Kung, Charles
van Wijk, Richard
HAEMATOLOGICA, 2021, 106 (01) : 238 - 249
[3] Red cell pyruvate kinase deficiency: from genetics to clinical manifestations
Zanella, A
Bianchi, P
BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY, 2000, 13 (01) : 57 - 81
[4] Red cell pyruvate kinase deficiency: molecular and clinical aspects
Zanella, A
Fermo, E
Bianchi, P
Valentini, G
BRITISH JOURNAL OF HAEMATOLOGY, 2005, 130 (01) : 11 - 25
[5] Red cell pyruvate kinase deficiency in Spain: A study of 15 cases
Montllor, Laura
del Mar Manu-Pereira, Maria
Llaudet-Planas, Esther
Gomez Ramirez, Pilar
Sevilla Navarro, Julian
Lluis Vives-Corrons, Joan
MEDICINA CLINICA, 2017, 148 (01): : 23 - 27
[6] Pyruvate kinase deficiency in 29 Turkish patients with two novel intronic variants
Gok, Veysel
Leblebisatan, Goksel
Gokcebay, Dilek Gurlek
Guler, Salih
Dogan, Muhammet Ensar
Bozdogan, Sevcan Tug
Yozgat, Ayca Koca
Ozcan, Alper
Sahinoglu, Esra Pekpak
Tokgoz, Huseyin
Cil, Metin
Sag, Sebnem Ozemri
Yilmaz, Ebru
Sasmaz, Hatice Ilgen
Evim, Melike Sezgin
Akbayram, Sinan
Karadogan, Meriban
Mutlu, Fatma Turkan
Boga, Ibrahim
Dogan, Burcu Yeter
Yarali, Nese
Caliskan, Uemran
Bisgin, Atil
Temel, Sehime Gulsun
Proven, Melanie
Gibson, Kate
Demir, Buesra Seniz
Saracoglu, Hatice
Eken, Ahmet
Karakukcu, Cigdem
Karakukcu, Musa
Gunes, Adalet Meral
Ozbek, Namik Yasar
Kilinc, Yurdanur
Patiroglu, Tuerkan
Ozdemir, Mehmet Akif
Roy, Noemi B. A.
Unal, Ekrem
BRITISH JOURNAL OF HAEMATOLOGY, 2024, 205 (01) : 236 - 242
[7] Red cell pyruvate kinase deficiency:: 17 new mutations of the PK-LR gene
Fermo, E
Bianchi, P
Chiarelli, LR
Cotton, F
Vercellati, C
Writzl, K
Baker, K
Hann, I
Rodwell, R
Valentini, G
Zanella, A
BRITISH JOURNAL OF HAEMATOLOGY, 2005, 129 (06) : 839 - 846
[8] Molecular Analyses of Pyruvate Kinase Deficient Turkish Patients from a Single Center
Unal, Sule
Gumruk, Fatma
PEDIATRIC HEMATOLOGY AND ONCOLOGY, 2015, 32 (05) : 354 - 361
[9] Pyruvate kinase deficiency as a cause of extreme hyperbilirubinemia in neonates from a polygamist community
Christensen, R. D.
Eggert, L. D.
Baer, V. L.
Smith, K. N.
JOURNAL OF PERINATOLOGY, 2010, 30 (03) : 233 - 236
[10] Pyruvate Kinase Function Correlates With Red Blood Cell Properties and Clinical Manifestations in Sickle Cell Disease
Traets, M. J. M.
Bos, J. F.
van Der Veen, S.
van Pelt, L.
van Dijk, M. J.
van Oirschot, B. A.
de Wilde, J. R. A.
Jans, J. J.
van Solinge, W. W.
Schols, S. E. M.
Lauw, M. N.
Cnossen, M. H.
Nur, E.
Biemond, B. J.
Rijneveld, A. W.
van Beers, E. J.
van Wijk, R.
Rab, M. A. E.
AMERICAN JOURNAL OF HEMATOLOGY, 2025, 100 (05) : 785 - 796

← 1 2 →