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Identification and Structure-Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors.

Ferreira de Freitas R, Harding RJ, Franzoni I, Ravichandran M, Mann MK, Ouyang H, Lautens M, Santhakumar V, Arrowsmith CH, Schapira M
J Med Chem 61 4517-4527 (2018)
Related entries: 6ce6, 6ce8, 6cec, 6ced, 6cee, 6cef

Cited: 9 times
EuropePMC logo PMID: 29741882

Abstract

HDAC6 plays a central role in the recruitment of protein aggregates for lysosomal degradation and is a promising target for combination therapy with proteasome inhibitors in multiple myeloma. Pharmacologically displacing ubiquitin from the zinc-finger ubiquitin-binding domain (ZnF-UBD) of HDAC6 is an underexplored alternative to catalytic inhibition. Here, we present the discovery of an HDAC6 ZnF-UBD-focused chemical series and its progression from virtual screening hits to low micromolar inhibitors. A carboxylate mimicking the C-terminal extremity of ubiquitin, and an extended aromatic system stacking with W1182 and R1155, are necessary for activity. One of the compounds induced a conformational remodeling of the binding site where the primary binding pocket opens up onto a ligand-able secondary pocket that may be exploited to increase potency. The preliminary structure-activity relationship accompanied by nine crystal structures should enable further optimization into a chemical probe to investigate the merit of targeting the ZnF-UBD of HDAC6 in multiple myeloma and other diseases.

Reviews citing this publication (3)

  1. Pharmacological Modulation of Ubiquitin-Proteasome Pathways in Oncogenic Signaling. Sharma A, Khan H, Singh TG, Grewal AK, Najda A, Kawecka-Radomska M, Kamel M, Altyar AE, Abdel-Daim MM. Int J Mol Sci 22 11971 (2021)
  2. Role of the zinc finger and SCAN domain-containing transcription factors in cancer. Huang M, Chen Y, Han D, Lei Z, Chu X. Am J Cancer Res 9 816-836 (2019)
  3. Regulation of Thermogenic Adipocyte Differentiation and Adaptive Thermogenesis Through Histone Acetylation. Ong BX, Brunmeir R, Zhang Q, Peng X, Idris M, Liu C, Xu F. Front Endocrinol (Lausanne) 11 95 (2020)

Articles citing this publication (6)

  1. Development of Selective Histone Deacetylase 6 (HDAC6) Degraders Recruiting Von Hippel-Lindau (VHL) E3 Ubiquitin Ligase. Yang K, Wu H, Zhang Z, Leisten ED, Nie X, Liu B, Wen Z, Zhang J, Cunningham MD, Tang W. ACS Med Chem Lett 11 575-581 (2020)
  2. Disrupting the HDAC6-ubiquitin interaction impairs infection by influenza and Zika virus and cellular stress pathways. Wang L, Moreira EA, Kempf G, Miyake Y, Oliveira Esteves BI, Fahmi A, Schaefer JV, Dreier B, Yamauchi Y, Alves MP, Plückthun A, Matthias P. Cell Rep 39 110736 (2022)
  3. Convergent micro-wave assisted synthesis of quinazolinone and its precursor using the bio-sourced solvent pinane. Richieu A, Bertrand P. RSC Adv 13 20646-20650 (2023)
  4. Discovery and Characterization of a Chemical Probe Targeting the Zinc-Finger Ubiquitin-Binding Domain of HDAC6. Harding RJ, Franzoni I, Mann MK, Szewczyk MM, Mirabi B, Ferreira de Freitas R, Owens DDG, Ackloo S, Scheremetjew A, Juarez-Ornelas KA, Sanichar R, Baker RJ, Dank C, Brown PJ, Barsyte-Lovejoy D, Santhakumar V, Schapira M, Lautens M, Arrowsmith CH. J Med Chem 66 10273-10288 (2023)
  5. ProxyBind: A compendium of binding sites for proximity-induced pharmacology. Rovers E, Liu L, Schapira M. Comput Struct Biotechnol J 20 6163-6171 (2022)
  6. Small Molecule Screen Identifies Non-catalytic USP3 Chemical Handle. Mann MK, Wolf E, Silva M, Kwak HA, Wilson B, Bolotokova A, Wilson DJ, Harding RJ, Schapira M. ACS Omega 9 917-924 (2024)


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