Structure-based development of novel substrate-type G9a inhibitors as epigenetic modulators for sickle cell disease treatment

• Published in: Bioorganic & medicinal chemistry letters Vol. 110; p. 129856
• Main Authors: Nishigaya, Yosuke, Takase, Shohei, Sumiya, Tatsunobu, Sato, Tomohiro, Niwa, Hideaki, Sato, Shin, Nakata, Akiko, Matsuoka, Seiji, Maemoto, Yuki, Hashimoto, Noriaki, Namie, Ryosuke, Honma, Teruki, Umehara, Takashi, Shirouzu, Mikako, Koyama, Hiroo, Yoshida, Minoru, Ito, Akihiro, Shirai, Fumiyuki
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.09.2024
• Subjects: Anemia, Sickle Cell - drug therapy; Crystallography, X-Ray; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Epigenesis, Genetic - drug effects; G9a inhibitor; Histocompatibility Antigens - metabolism; Histone-Lysine N-Methyltransferase - antagonists & inhibitors; Histone-Lysine N-Methyltransferase - metabolism; Humans; Molecular Structure; Sickle cell disease; Structure-Activity Relationship; Structure-based optimization; Surface plasmon resonance analysis; X-ray crystallography; SANTZUMQHHSQMN-UHFFFAOYSA-N; DIEA; RNA; LPSQWMJVEOJPJL-UHFFFAOYSA-N; FJJHERPTGMLTTQ-UHFFFAOYSA-N; TFA; LPDWBZXHCHXSFX-UHFFFAOYSA-N; X-ray crystallography; THF; Boc; HOBt; Cbz; PHVLBOPWTRESRO-UHFFFAOYSA-N; HATU; DMF; HYKGKHZOKXZYFD-UHFFFAOYSA-N; Sickle cell disease; SANTZUMQHHSQMN-QHCPKHFHSA-N; G9a inhibitor; NANMKEQAFZLLPL-UHFFFAOYSA-N; EDCI; LPSQWMJVEOJPJL-KRWDZBQOSA-N; UIXUCUAPLODAJE-NRFANRHFSA-N; QUIAVPZNXWKBRS-UHFFFAOYSA-N; AHKWDHWEVOFKRW-UHFFFAOYSA-N; FKYWIFNZDJPACP-UHFFFAOYSA-N; DMT-MM; UIXUCUAPLODAJE-UHFFFAOYSA-N; FJJHERPTGMLTTQ-NRFANRHFSA-N; JBJZSRREPKULDQ-UHFFFAOYSA-N; DIQHUQXFMQZDSL-UHFFFAOYSA-N; Surface plasmon resonance analysis; Structure-based optimization; UKADGRMLLXXBGY-UHFFFAOYSA-N; KZSVNOBORLSDPC-UHFFFAOYSA-N; KCDCUNWZSBKGGZ-UHFFFAOYSA-N; IPE
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2024.129856

[Display omitted] The discovery and development of structurally distinct lysine methyltransferase G9a inhibitors have been the subject of intense research in epigenetics. Structure-based optimization was conducted, starting with the previously reported seed compound 7a and lead to the identification of a highly potent G9a inhibitor, compound 7i (IC50 = 0.024 μM). X-ray crystallography for the ligand–protein interaction and kinetics study, along with surface plasmon resonance (SPR) analysis, revealed that compound 7i interacts with G9a in a unique binding mode. In addition, compound 7i caused attenuation of cellular H3K9me2 levels and induction of γ-globin mRNA expression in HUDEP-2 cells in a dose-dependent manner.