Histone Deacetylase 6-Selective Inhibitors and the Influence of Capping Groups on Hydroxamate-Zinc Denticity

Porter, Nicholas J.; Osko, Jeremy D.; Diedrich, Daniela; Kurz, Thomas; Hooker, Jacob M.; Hansen, Finn K.; Christianson, David W.

doi:10.1021/acs.jmedchem.8b01013

Cited by 139Histone Deacetylase Inhibitors ResearchEnzyme function and inhibitionEnzyme Structure and Function

Histone Deacetylase 6-Selective Inhibitors and the Influence of Capping Groups on Hydroxamate-Zinc Denticity

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Porter, Nicholas J., Osko, Jeremy D., Diedrich, Daniela, Kurz, Thomas, Hooker, Jacob M., Hansen, Finn K., Christianson, David W.·2018·Journal of Medicinal Chemistry

DOI 10.1021/acs.jmedchem.8b01013PMC PMC6136958

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Abstract

Four crystal structures are presented of histone deacetylase 6 (HDAC6) complexes with para -substituted phenylhydromaxamate inhibitors, including bulky peptoids. These structures provide insight regarding the design of capping groups that confer selectivity for binding to HDAC6, specifically with regard to interactions in a pocket formed by the L1 loop. Capping group interactions may also influence hydroxamate-Zn 2+ coordination with monodentate or bidentate geometry.

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Recent work on HDAC6/inhibitor complexes demonstrates that L1 loop conformational stability is important for interactions of L1 loop residues with inhibitor capping groups to achieve HDAC6 selectivity inhibition.
“the recent work on HDAC6/inhibitor complexes demonstrate that L1 loop conformational stability is important for the interactions of L1 loop residues with inhibitors capping groups to achieve HDAC6 selectivity inhibition 42-46”
From Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants (2018) · cites this paper as [45]
In Results and Discussion, the paper shows inhibitor capping groups contacting the L1 loop pocket and says those interactions are important for HDAC6 selectivity. It describes the loop as relatively rigid, but says its pre-formed structure *presumably* contributes to selective binding; the citing sentence presents that proposed role as demonstrated. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Selective inhibition appears to rely on small structural differences between HDAC1-3 and HDAC6 and on small thermodynamic differences in selective inhibitor binding.
“Selective inhibition appears to rely on small structural differences between HDAC1-3 and HDAC6 and on small thermodynamic differences in selective inhibitor binding 42-46 .”
From Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants (2018) · cites this paper as [45]
In Results and Discussion (L1 loop pocket; page unavailable), the paper says the L1 loop in HDAC1–3 is shifted about 1 Å relative to HDAC6 and suggests this difference helps explain selective inhibition. It also discusses entropy gain in selective inhibitor binding and small energy differences between zinc-coordination modes, but does not establish that small thermodynamic differences between HDAC1–3 and HDAC6 govern inhibitor selectivity. (LLM, conf=0.83)
Experimental — accuracy not yet measured

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[38]Winn MD, Ballard CC, Cowtan KD, Dodson EJ, Emsley P, Evans PR, Keegan RM, Krissinel EB, Leslie AGW, McCoy A, McNicholas SJ, Murshudov GN, Pannu NS, Potterton EA, Powell HR, Read RJ, Vagin A, Wilson KS Overview of the CCP4 suite and current developments. Acta Crystallogr., Sect. D: Biol. Crystallogr 2011, 67, 235– 242. 21460441 PMC3069738
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Mechanistic Exploration of Methionine 274 Acting as a “Switch” of the Selective Pocket Involved in HDAC8 Inhibition: An in Silico Study
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Ronald C.D. Breslow (1931–2017): A career in review
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First Fluorescent Acetylspermidine Deacetylation Assay for HDAC10 Identifies Inhibitors of Neuroblastoma Cell Colony Growth That Increase Lysosome AccumulationPreprint
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Recommended Tool Compounds: Isoform- and Class-Specific Histone Deacetylase Inhibitors
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A new computational cross-structure-activity relationship (C-SAR) approach applies to a selective HDAC6 inhibitor dataset for accelerated structure development
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In silico study of the synergistic anti-tumor effect of hybrid topoisomerase-HDAC inhibitors
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First Fluorescent Acetylspermidine Deacetylation Assay for HDAC10 Identifies Inhibitors of Neuroblastoma Cell Colony Growth That Increase Lysosome AccumulationPreprint
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Ar-A014418-Based Dual Glycogen Synthase Kinase 3β / Histone Deacetylases Inhibitors as Potential Therapeutics for Alzheimer's DiseasePreprint
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Losson, H. (2020) · doi:10.70675/4bf04224zf884z44dfz8928zaff56bbaeb88
Biochemical, biophysical and structural study of proteins associated to human diseases : tcDAC2 and ADAT complex
Ramos‐Morales, E. (2021) · theses.fr (ABES) · doi:10.70675/c6b28473zf6b6z4024z99bfz05629f0484d7
Macrophage-Centric Phenotypic Screening Identifies Tetrazolone-Based HDAC6 Inhibitors That Reprogram the Tumor Immune Microenvironment and Improve Immune Checkpoint Blockade
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Exploring Structural Determinants of Inhibitor Affinity and Selectivity in Complexes with Histone Deacetylase 6
Osko, J. D., Porter, N. J., Poli, A. N. R., Xiao, Y., Rokka, J., Jung, M., Hooker, J. M., Salvino, J. M., & Christianson, D. W. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01540 · Cited by 56 · see citing works
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Structural determinants of affinity and selectivity in the binding of inhibitors to histone deacetylase 6
Osko, J. D., & Christianson, D. W. (2020) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2020.127023 · Cited by 56 · see citing works
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Entropy as a Driver of Selectivity for Inhibitor Binding to Histone Deacetylase 6
Porter, N. J., Wagner, F. F., & Christianson, D. W. (2018) · Biochemistry · doi:10.1021/acs.biochem.8b00367 · Cited by 64 · see citing works
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Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors
Porter, N. J., Mahendran, A., Breslow, R., & Christianson, D. W. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1718823114 · Cited by 190 · see citing works
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A Novel Zinc Binding Group for HDAC6 Inhibition
Cragin, A. D., Watson, P. R., König, B., Hansen, F. K., & Christianson, D. W. (2022) · The FASEB Journal · doi:10.1096/fasebj.2022.36.s1.r3604 · Cited by 10 · see citing works
Self-citation

Authors: Porter, N. J., Osko, J. D., Diedrich, D., Kurz, T., Hooker, J. M., Hansen, F. K., & Christianson, D. W.
Affiliations: University of Pennsylvania (US)
Heinrich Heine University Düsseldorf (DE)
Harvard University (US)
Corresponding author: Christianson, David W.
ORCID: Porter, Nicholas J.
Osko, Jeremy D.
Kurz, Thomas
Hooker, Jacob M.
Hansen, Finn K.
Christianson, David W.
Venue: Journal of Medicinal Chemistry
Publisher: American Chemical Society (ACS)
Published: 2018-08-17
Volume: 61
Issue: 17
Pages: 8054-8060
ISSN: 0022-2623 (ISSN-L)
1520-4804
DOI: 10.1021/acs.jmedchem.8b01013
PMC: PMC6136958
OpenAlex: W2887296525
Cited by: 111
References: 43
Citations by year: 2026: 11 · 2025: 16 · 2024: 8 · 2023: 8 · 2022: 10 · 2021: 16 · 2020: 21 · 2019: 15 · 2018: 6
FWCI: 6.31
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Journal of Medicinal Chemistry (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
Funders: Deutsche Forschungsgemeinschaft (HA 7783/1-1)
National Institute of General Medical Sciences (GM49758)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Keywords: HDAC6, HDAC6 inhibitors, capping groups, peptoids, L1 loop, enzyme selectivity, crystal structure
MeSH terms: Histone Deacetylase 6, Animals, Hydroxamic Acids, Protein Conformation, Zebrafish, Zinc, Molecular Structure, Crystallography, X-Ray, Zebrafish Proteins, Histone Deacetylase Inhibitors, Coordination Complexes

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Histone Deacetylase 6-Selective Inhibitors and the Influence of Capping Groups on Hydroxamate-Zinc Denticity

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