2. Academic Validation
  3. Discovery of novel 4-aminobenzamide derivatives as small molecule CBX2 inhibitors

Discovery of novel 4-aminobenzamide derivatives as small molecule CBX2 inhibitors

  • Bioorg Med Chem Lett. 2026 Apr:133:130526. doi: 10.1016/j.bmcl.2025.130526.
Yuichiro Kawamoto 1,  Shohei Takase 2,  Kumar Ashutosh 3,  Hiroki Maruo 4,  Yuki Maemoto 2,  Kam Y J Zhang 3,  Hisanaka Ito 2,  Akihiro Ito 5
Affiliations

Affiliations

  • 1 School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. Electronic address: [email protected].
  • 2 School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
  • 3 Laboratory for Structural Bioinformatics, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-004, Japan.
  • 4 School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan; Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
  • 5 School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan; Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Drug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: [email protected].
PMID: 41478308 DOI: 10.1016/j.bmcl.2025.130526
Abstract

CBX2 protein plays an important role in methyl-lysine recognition involved in epigenetic regulation. In contrast to CBX7 modulators, there are few reported CBX2 inhibitors, most of which are peptidergic molecules. This fact encouraged us to search non-peptidic small molecule CBX2 inhibitors with sufficient cell permeability by in silico screening followed by synthetic evolution. In virtual screening, we identified a 4-aminobenzamide scaffold with high in silico score and Nano BRET activities. Based on several in silico hit compounds, we synthesized a series of 4-aminobenzamide derivatives and tested their Nano BRET activities. Among them, compound 37 showed moderate CBX2 inhibitory activity with an IC50 value of 9.6 μM, a potential lead compound. This is a first small molecule CBX2 inhibitor identified as a result of SAR studies and lead optimization by medicinal chemistry.

Keywords

Docking study; In silico screening; Medicinal chemistry; Non-peptidic small molecule CBX2 inhibitors.

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