2. Academic Validation
  3. Potent and orally active purine-based fetal hemoglobin inducers for treating β-thalassemia and sickle cell disease

Potent and orally active purine-based fetal hemoglobin inducers for treating β-thalassemia and sickle cell disease

  • Eur J Med Chem. 2021 Jan 1:209:112938. doi: 10.1016/j.ejmech.2020.112938.
Zheng-Sheng Lai 1,  Teng-Kuang Yeh 2,  Yu-Chi Chou 3,  Tsu Hsu 2,  Cheng-Tai Lu 2,  Fang-Chun Kung 2,  Ming-Yen Hsieh 4,  Chun-Hung Lin 4,  Chiung-Tong Chen 2,  Che-Kun James Shen 5,  Weir-Torn Jiaang 6
Affiliations

Affiliations

  • 1 Institute of Molecular Biology, Academia Sinica, Taipei, 11529, Taiwan, ROC; Institute of Molecular Medicine, College of Medicine, National Taiwan University, No.7.Chung San South Road, Taipei, 10002, Taiwan, ROC.
  • 2 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli Country, 35053, Taiwan, ROC.
  • 3 Biomedical Translation Research Center (BioTReC), Academia Sinica, Taipei, 11529, Taiwan, ROC.
  • 4 Institute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan, ROC.
  • 5 Institute of Molecular Biology, Academia Sinica, Taipei, 11529, Taiwan, ROC.
  • 6 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli Country, 35053, Taiwan, ROC. Electronic address: wtjiaang@nhri.org.tw.
PMID: 33109398 DOI: 10.1016/j.ejmech.2020.112938
Abstract

Reactivation of fetal hemoglobin (HbF) expression by therapeutic agents has been suggested as an alternative treatment to modulate anemia and the related symptoms of severe β-thalassemia and sickle cell disease (SCD). Hydroxyurea (HU) is the first US FDA-approved HbF inducer for treating SCD. However, approximately 25% of the patients with SCD do not respond to HU. A previous study identified TN1 (1) as a small-molecule HbF inducer. However, this study found that the poor potency and oral bioavailability of compound 1 limits the development of this inducer for clinical use. To develop drug-like compounds, further structure-activity relationship studies on the purine-based structure of 1 were conducted. Herein, we report our discovery of a more potent inducer, compound 13a, that can efficiently induce γ-globin gene expression at non-cytotoxic concentrations. The molecular mechanism of 13a, for the regulation HbF expression, was also investigated. In addition, we demonstrated that oral administration of 13a can ameliorate anemia and the related symptoms in SCD mice. The results of this study suggest that 13a can be further developed as a novel agent for treating hemoglobinopathies, such as β-thalassemia and SCD.

Keywords

Fetal hemoglobin; Inducer; Sickle cell disease; β-Thalassemia.

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