Discovery of an HDAC2-Selective Inhibitor via Enzyme−Inhibitor-Binding Thermodynamics/Kinetics as a Prospective Neurological Disorder Drug
Abstract In this study, we identified KTT-1 (12) as an HDAC2-selective inhibitor through in vitro evaluations based on both thermodynamics and kinetics of the enzyme−inhibitor binding. This approach stands in sharp contrast to conventional drug discovery research, which usually focuses only on thermodynamics. An X-ray crystallography study on HDAC2 complexed with 12 in combination with quantum chemical calculations on model compounds suggested that the 2-furanyl group of 12 contributes to the selective HDAC2 inhibition. In our cellular assays, 12 preferentially inhibited HDAC2 over its highly homologous HDAC1 and promoted neurite outgrowth of neuro-2a cells. Furthermore, treatment of mice with 12 improved the memory and depression-like behavior of stress-vulnerable mice. The results indicate that 12 is a promising lead compound for neurological disorders such as Alzheimer’s disease and depression and demonstrate that inhibitor evaluations that combine enzyme−inhibitor-binding thermodynamics and kinetics are useful tools for drug discovery research.
Authors
- Shusaku Uchida (ORCID: https://orcid.org/0000-0002-1451-6222)
- Yasunobu Yamashita (ORCID: https://orcid.org/0000-0001-5078-5940)
- Ken‐ichi Kusakabe (ORCID: https://orcid.org/0000-0001-9055-8267)
- Remy Narozny
- Takashi Kurohara (ORCID: https://orcid.org/0000-0003-4228-3478)
- T Tojo (ORCID: https://orcid.org/0000-0003-3803-8824)
- Takayoshi Suzuki (ORCID: https://orcid.org/0000-0003-2439-879X)
- Yukihiro Itoh (ORCID: https://orcid.org/0000-0002-3410-2924)
- Naotaka Horiguchi (ORCID: https://orcid.org/0000-0001-8820-2245)
- Hiroyuki Kusuhara (ORCID: https://orcid.org/0000-0002-3641-8746)
- Alexander M. A. van der Wiel (ORCID: https://orcid.org/0000-0003-4499-189X)
- Kayoko Kanamitsu (ORCID: https://orcid.org/0000-0002-7576-9389)
- Yuka Miyake
- Hiroko Ono
- Ying Li
- Rio Furutani
- Ritesh Singh
Institutions
- University of Delhi (IN)
- Kyoto Prefectural University (JP)
- Kyoto University (JP)
- Nagoya City University (JP)
- National Institute of Technology, Suzuka College (JP)
- Kyoto University Hospital (JP)
- Institute of Science Tokyo (JP)
- The University of Tokyo (JP)
- Futaba (Japan) (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-10-08
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c03068
- Primary Topic
- Histone Deacetylase Inhibitors Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00