Design and Synthesis of Dihydroxamic Acids as HDAC6/8/10 Inhibitors

Michael Morgen; Raphael R Steimbach; Magalie Géraldy; Lars Hellweg; Peter Sehr; Johannes Ridinger; Olaf Witt; Ina Oehme; Corey J Herbst-Gervasoni; Jeremy D Osko; Nicholas J Porter; David W Christianson; Nikolas Gunkel; Aubry K Miller

doi:10.1002/cmdc.202000149

Design and Synthesis of Dihydroxamic Acids as HDAC6/8/10 Inhibitors

ChemMedChem. 2020 Jul 3;15(13):1163-1174. doi: 10.1002/cmdc.202000149. Epub 2020 May 13.

Authors

Michael Morgen¹, Raphael R Steimbach^{1

2}, Magalie Géraldy¹, Lars Hellweg¹, Peter Sehr³, Johannes Ridinger^{4

5

6}, Olaf Witt^{4

5

6

7}, Ina Oehme^{4

5

6}, Corey J Herbst-Gervasoni⁸, Jeremy D Osko⁸, Nicholas J Porter⁸, David W Christianson⁸, Nikolas Gunkel^{1

7}, Aubry K Miller^{1

7}

Affiliations

¹ Cancer Drug Development Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
² Faculty of Biosciences, University of Heidelberg, 69120, Heidelberg, Germany.
³ Chemical Biology Core Facility, European Molecular Biology Laboratory (EMBL), 69117, Heidelberg, Germany.
⁴ Hopp Children's Cancer Center Heidelberg (KiTZ), 69120, Heidelberg, Germany.
⁵ Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
⁶ Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, 69120, Heidelberg, Germany.
⁷ German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
⁸ Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA.

Abstract

We report the synthesis and evaluation of a class of selective multitarget agents for the inhibition of HDAC6, HDAC8, and HDAC10. The concept for this study grew out of a structural analysis of the two selective inhibitors Tubastatin A (HDAC6/10) and PCI-34051 (HDAC8), which we recognized share the same N-benzylindole core. Hybridization of the two inhibitor structures resulted in dihydroxamic acids with benzyl-indole and -indazole core motifs. These substances exhibit potent activity against HDAC6, HDAC8, and HDAC10, while retaining selectivity over HDAC1, HDAC2, and HDAC3. The best substance inhibited the viability of the SK-N-BE(2)C neuroblastoma cell line with an IC₅₀ value similar to a combination treatment with Tubastatin A and PCI-34051. This compound class establishes a proof of concept for such hybrid molecules and could serve as a starting point for the further development of enhanced HDAC6/8/10 inhibitors.

Keywords: HDAC10; HDAC8; inhibitors; polypharmacology; targeted therapy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Histone Deacetylase 6 / antagonists & inhibitors*
Histone Deacetylase 6 / metabolism
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / metabolism
Humans
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology*
Molecular Structure
Repressor Proteins / antagonists & inhibitors*
Repressor Proteins / metabolism
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Histone Deacetylase Inhibitors
Hydroxamic Acids
Repressor Proteins
HDAC6 protein, human
HDAC8 protein, human
Histone Deacetylase 6
Histone Deacetylases

Abstract

Publication types

MeSH terms

Substances

Grants and funding