2. Academic Validation
  3. Selective and Bioavailable HDAC6 2-(Difluoromethyl)-1,3,4-oxadiazole Substrate Inhibitors and Modeling of Their Bioactivation Mechanism

Selective and Bioavailable HDAC6 2-(Difluoromethyl)-1,3,4-oxadiazole Substrate Inhibitors and Modeling of Their Bioactivation Mechanism

  • J Med Chem. 2023 Oct 26;66(20):14188-14207. doi: 10.1021/acs.jmedchem.3c01269.
Lena Ripa 1,  Jenny Sandmark 2,  Glyn Hughes 1,  Igor Shamovsky 1,  Anders Gunnarsson 2,  Julia Johansson 3,  Antonio Llinas 1,  Mia Collins 1,  Bomi Jung 2,  Anna Novén 2,  Nils Pemberton 1,  Mickael Mogemark 3,  Yao Xiong 4,  Qing Li 4,  Stefan Tångefjord 2,  Margareta Ek 2,  Annika Åstrand 1
Affiliations

Affiliations

  • 1 Respiratory & Immunology (R&I), Research and Early Development, BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden.
  • 2 Discovery Sciences, Research and Early Development, BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden.
  • 3 Clinical Pharmacology and Safety Sciences, Research and Early Development, BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden.
  • 4 Pharmaron Beijing, Co. Ltd., No. 6, Taihe Road, BDA, Beijing 100176, China.
PMID: 37797307 DOI: 10.1021/acs.jmedchem.3c01269
Abstract

Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family mainly targeting cytosolic nonhistone substrates, such as α-tubulin, cortactin, and heat shock protein 90 to regulate cell proliferation, metastasis, invasion, and mitosis in tumors. We describe the identification and characterization of a series of 2-(difluoromethyl)-1,3,4-oxadiazoles (DFMOs) as selective nonhydroxamic acid HDAC6 inhibitors. By comparing structure-activity relationships and performing quantum mechanical calculations of the HDAC6 catalytic mechanism, we show that potent oxadiazoles are electrophilic substrates of HDAC6 and propose a mechanism for the bioactivation. We also observe that the inherent electrophilicity of the oxadiazoles makes them prone to degradation in water solution and the generation of potentially toxic products cannot be ruled out, limiting the developability for chronic diseases. However, the oxadiazoles demonstrate high oral bioavailability and low in vivo clearance and are excellent tools for studying the role of HDAC6 in vitro and in vivo in rats and mice.

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