A quest by researchers to understand an enzyme inhibitor has led to the development of a novel candidate for the treatment of sickle cell disease, a heritable genetic disorder that affects millions of people worldwide.

Sickle cell disease (SCD)—a disorder caused by mutations in the β-globin gene—can be transmitted from parent to offspring. The clinical manifestations of SCD can be offset by inducing the production of fetal γ-globin, and one promising type of therapeutic agent for combating SCD is inhibitors of the histone methyltransferase G9a that are associated with γ-globin re-activation and fetal hemoglobin production. However, their precise mechanism remains elusive. The team, led by researchers from RIKEN and the Tokyo University of Pharmacy and Life Sciences, was recently able to explain their mechanism of action and also develop a promising therapeutic candidate, RK-701, for treating SCD.

In a study recently published in Nature Communications, the team led by Minoru Yoshida at RIKEN and Akihiro Ito at the Tokyo University of Pharmacy and Life Sciences have not only elucidated the mechanism of G9a inhibitor action but also revealed the therapeutic potential of a novel G9a inhibitor called “RK-701.”

“We succeeded in developing RK-701, a specific and low-toxic inhibitor of the histone methyltransferase G9a, with a novel chemical scaffold. RK-701 induces fetal γ-globin expression in human erythroid cells as well as embryonic globin expression in mice and shows greater efficacy than hydroxyurea, an existing therapeutic agent that is used to treat SCD,” says Ito.

RK-701 is highly selective and non-genotoxic. In other words, it does not bind non-specifically to off-target locations and does not damage the host DNA. Although hydroxyurea has long been used to treat SCD, its toxicity is a serious concern. RK-701 seems to have better efficacy and safety than hydroxyurea. Moreover, it upregulates BGLT3 long non-coding RNAs (lncRNAs). It is known that lncRNAs are not translated into proteins. However, they have been increasingly found to be involved in the regulation of gene expression. By upregulating the BGLT3 gene, it ensures the expression of its lncRNA, thus triggering the production of the SCD combating γ-globin and fetal hemoglobin.

Yoshida, who leads the Chemical Genomics Research Group at RIKEN Center for Sustainable Resource Science, adds, “We noticed that the long noncoding RNA of BGLT3 upregulated by RK-701 has a universal role in inducing fetal hemoglobin expression, which underscores its efficacy as a therapeutic target for SCD.”

A series of in-depth experiments with adequate controls finally unleashed the molecular mechanism of G9a-mediated γ-globin gene expression in human erythroid cells.

Shohei Takase from the Tokyo University of Pharmacy and Life Sciences, also a coauthor of the study, remarks, “RK-701 selectively upregulates BGLT3 by inhibiting the recruitment of two major γ-globin repressors in complex with G9a onto the BGLT3 gene locus through CHD4, a component of the NuRD complex. Remarkably, BGLT3 is indispensable for γ-globin induction by not only RK-701 but also hydroxyurea and other inducers. The universal role of BGLT3 in γ-globin induction suggests its importance in SCD treatment.”

Ito adds, “Our study clearly demonstrates that BGLT3 is the universal activator for fetal globin gene expression. The essential role of BGLT3 lncRNA in the induction of fetal hemoglobin expression highlights its role as an extremely attractive therapeutic target for SCD.”

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Contact

Minoru Yoshida, Group Director

Chemical Genomics Research Group

RIKEN Center for Sustainable Resource Science

Jens Wilkinson
RIKEN International Affairs Division
Tel: +81-(0)48-462-1225
Email: jens.wilkinson [at] riken.jp