A new candidate therapeutic for sickle cell disease developed

January 12, 2023

RK-701, a new inhibitor of histone methyltransferase G9a

The cooperative research group, including the RIKEN CSRS, Tokyo University of Pharmacy and Life Sciences, and the Institute of Microbial Chemistry, conducted a structure-activity relationship study of more than 1,000 derivatives based on hit compounds obtained by high-throughput screening and developed a novel inhibitor RK-701 of histone methyltransferase G9a. They further found that BGLT3 long non-coding RNA (BGLT3 lncRNA) induced by RK-701 plays a universal role in fetal hemoglobin (HbF) induction in patients with sickle cell disease (SCD).

In this study, the researchers developed a novel potent G9a inhibitor RK-701 that is specific and low toxic. The reinduction of HbF, which is present in fetuses but disappears after birth, has been proposed as a strategy to treat SCD, a heritable disorder. RK-701 induced the expression of HbF more efficiently than hydroxyurea, the preexisting therapeutic agent for SCD. The research group further demonstrated that BGLT3 IncRNA plays a crucial role in the reactivation of HbF by not only RK-701 but other inducers, including hydroxyurea.

These results would contribute to developing new treatments for SCD.

Original article
Nature Communications doi:10.1038/s41467-022-35404-0
S. Takase, T. Hiroyama, F. Shirai, Y. Maemoto, A. Nakata, M. Arata, S. Matsuoka, T. Sonoda, H. Niwa, S. Sato, T. Umehara, M. Shirouzu, Y. Nishigaya, T. Sumiya, N. Hashimoto, R. Namie, M. Usui, T. Ohishi, S. Ohba, M. Kawada, Y. Hayashi, H. Harada, T. Yamaguchi, Y. Shinkai, Y. Nakamura, M. Yoshida, A. Ito,
"A specific G9a inhibitor unveils BGLT3 lncRNA as a universal mediator of chemically induced fetal globin gene expression".
Akihiro Ito; Senior Visiting Scientist
Minoru Yoshida; Group Director
Chemical Genomics Research Group