Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor
Open accessAbstract
Fragment-based ligand discovery was successfully applied to histone deacetylase HDAC2. In addition to the anticipated hydroxamic acid- and benzamide-based fragment screening hits, a low affinity (∼1 mM) α-amino-amide zinc binding fragment was identified, as well as fragments binding to other regions of the catalytic site. This alternative zinc-binding fragment was further optimized, guided by the structural information from protein–ligand complex X-ray structures, into a sub-μM, brain penetrant, HDAC2 inhibitor ( 17 ) capable of modulating histone acetylation levels in vivo .
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Compound 11, a ketone, has been shown to exhibit class I HDAC selectivity with nanomolar potency.
“Compound 11, a ketone, has also been shown to exhibit class I HDAC selectivity with nanomolar potency [90].”
From Medicinal chemistry advances in targeting class I histone deacetylases (2023) · cites this paper as [90]
Compound 12 has picomolar potency towards class I HDACs likely due to improved optimization of the cap group and the visibly close resemblance of the ZBG to hydroxamates.
“Compound 12 has picomolar potency towards class I HDACs which is likely due to the improved optimization of the cap group, and the visibly close resemblance of the ZBG to hydroxamates, which are intrinsically quite potent against all HDACs.”
From Medicinal chemistry advances in targeting class I histone deacetylases (2023) · cites this paper as [90]
Cites
Lauffer, B. E. L., Mintzer, R., Fong, R., Mukund, S., Tam, C., Zilberleyb, I., Flicke, B., Ritscher, A., Fedorowicz, G., Vallero, R., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.490706 · Cited by 429 · see citing works
Whitehead, L., Dobler, M. R., Radetich, B., Zhu, Y., Atadja, P. W., Claiborne, T., Grob, J. E., McRiner, A., Pancost, M. R., Patnaik, A., et al. (2011) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2011.06.030 · Cited by 164 · see citing works
Kinetically selective inhibitors of histone deacetylase 2 (HDAC2) as cognition enhancers
Wagner, F. F., Zhang, Y.-L., Fass, D. M., Joseph, N., Gale, J. P., Weïwer, M., McCarren, P., Fisher, S. L., Kaya, T., Zhao, W.-N., et al. (2015) · Chemical Science · doi:10.1039/c4sc02130d · Cited by 104 · see citing works
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Medicinal chemistry advances in targeting class I histone deacetylases
Abdallah, D. I., de Araujo, E. D., Patel, N. H., Hasan, L. S., Moriggl, R., Krämer, O. H., & Gunning, P. T. (2023) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2023.00166 · Cited by 15 · see citing works
“Finally, compound 13, an orally active, brain-penetrant HDAC2 inhibitor, has recently been discovered through fragment-based drug discovery [91].”
Background
- Authors
- Tamanini, E., Miyamura, S., Buck, I. M., Cons, B. D., Dawson, L., East, C., Futamura, T., Goto, S., Griffiths-Jones, C., Hashimoto, T., Heightman, T. D., Ishikawa, S., Ito, H., Kaneko, Y., Kawato, T., Kondo, K., Kurihara, N., McCarthy, J. M., Mori, Y., Nagase, T., Nakaishi, Y., Reeks, J., Sato, A., Schöpf, P., Tai, K., Tamai, T., Tisi, D., & Woolford, A. J.-A.
- Affiliations
- Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
- Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan
- Corresponding author
- Tamanini, Emiliano
- Miyamura, Shin
- ORCID
- Venue
- ACS Medicinal Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2022-09-06
- Volume
- 13
- Issue
- 10
- Pages
- 1591-1597
- ISSN
- 1948-5875 (ISSN-L)
- PMC
- PMC9575179
- OpenAlex
- W4294761837
- Cited by
- 25
- References
- 3
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 7 · 2023: 1
- FWCI
- 1.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- ACS Medicinal Chemistry Letters (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Keywords
- HDAC2 inhibitors, histone deacetylase, brain-penetrant drugs, orally active drugs, hydroxamic acids, benzamide, histone acetylation, structure-guided optimization, protein-ligand complex
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