Development of a selective HDAC inhibitor aimed at reactivating the HIV latent reservoir

Clausen, Dane J.; Liu, Jian; Yu, Wei; Duffy, Joseph; Chung, Caroline; Myers, Robert W.; Klein, Daniel; Fells, James I.; Holloway, Kate; Jin, Wei; Wu, Guoxin; Howell, Bonnie J.; Barnard, Richard; Kozlowski, Joseph A.

doi:10.1016/j.bmcl.2020.127367

Cited by 15 publications

(15 citation statements)

References 20 publications

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“…Pharmacokinetic analysis showed an improved profile of oxazole compared to imidazole moieties with medium–high blood–brain barrier permeability in porcine brain endothelial cells and high to modest in vivo bioavailability, as well as a plasma half-life of 3.3–3.7 h and moderate clearance (20 mL⋅min −1 ⋅kg −1 ) [ 101 ]. Similar scaffolds were used by Yu et al [ 121 ] and Clausen et al [ 127 ] for HIV treatment. In the “shock and kill” strategy, HDACs acts as the “shock”, potentially reactivating the latent HIV reservoir and, thus, inducing the HIV gene transcription in resting cells, making them susceptible to “kill” strategies.…”

Section: Ketone Warheadsmentioning

confidence: 97%

“…As Bresciani et al [ 101 ] noticed and Yu et al [ 121 ] calculated, oxazole derivatives 57b and 57c exhibited twofold better permeability, explaining the improved pharmacokinetic properties. In 2020, Clausen et al [ 127 ] identified 58 and 59 as lead compounds and determined their pharmacokinetic properties in rats. Compounds 58 and 59 showed very good inhibitory activity of 1.9 nM and 3.8 nM (HDAC1), 18.1 nM and 19.7 nM (HDAC2), and 2.5 nM and 2.9 nM (HDAC3), respectively.…”

Section: Ketone Warheadsmentioning

confidence: 99%

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Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

Frühauf

Meyer‐Almes

2021

Molecules

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Histone deacetylases (HDACs) remove acetyl groups from acetylated lysine residues and have a large variety of substrates and interaction partners. Therefore, it is not surprising that HDACs are involved in many diseases. Most inhibitors of zinc-dependent HDACs (HDACis) including approved drugs contain a hydroxamate as a zinc-binding group (ZBG), which is by far the biggest contributor to affinity, while chemical variation of the residual molecule is exploited to create more or less selectivity against HDAC isozymes or other metalloproteins. Hydroxamates have a propensity for nonspecificity and have recently come under considerable suspicion because of potential mutagenicity. Therefore, there are significant concerns when applying hydroxamate-containing compounds as therapeutics in chronic diseases beyond oncology due to unwanted toxic side effects. In the last years, several alternative ZBGs have been developed, which can replace the critical hydroxamate group in HDACis, while preserving high potency. Moreover, these compounds can be developed into highly selective inhibitors. This review aims at providing an overview of the progress in the field of non-hydroxamic HDACis in the time period from 2015 to present. Formally, ZBGs are clustered according to their binding mode and structural similarity to provide qualitative assessments and predictions based on available structural information.

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Section: Ketone Warheadsmentioning

confidence: 97%

Section: Ketone Warheadsmentioning

confidence: 99%

Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

Frühauf

Meyer‐Almes

2021

Molecules

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“…In the attempt to search for HDAC isoform selective inhibitors, we recently reported two series of HDACs 1, 2, 3 inhibitors: the ethyl ketone series exemplified by compound 1 and the aryl ketone series exemplified by compound 2 (Figure ). − These class I HDAC inhibitors showed efficacy for HIV latency activation in a Jurkat 2C4 cell model and induction of HIV gag p24 protein in patient latent CD4 + T cells . In the process of determining the required HDAC subtype inhibition for HIV latency activation, we demonstrated that inhibition of only HDAC1, 2 by compound 3 did not show any cellular activity in the HIV latency activation .…”

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confidence: 90%

Discovery of Highly Selective and Potent HDAC3 Inhibitors Based on a 2-Substituted Benzamide Zinc Binding Group

Liu

Kelly

et al. 2020

ACS Med. Chem. Lett.

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The selectivity of histone deacetylase inhibitors (HDACis) is greatly impacted by the zinc binding groups. In an effort to search for novel zinc binding groups, we applied a parallel medicinal chemistry (PMC) strategy to quickly synthesize substituted benzamide libraries. We discovered a series containing 2-substituted benzamides as the zinc binding group which afforded highly selective and potent HDAC3 inhibitors, exemplified by compound 16 with a 2-methylthiobenzamide. Compound 16 inhibited HDAC3 with an IC 50 of 30 nM and with unprecedented selectivity of >300-fold over all other HDAC isoforms. Interestingly, a subtle change of the 2-methylthio to a 2-hydroxy benzamide in 20 retains HDAC3 potency but loses all selectivity over HDAC 1 and 2. This significant difference in selectivity was rationalized by X-ray crystal structures of HDACis 16 and 20 bound to HDAC2, revealing different binding modes to the catalytic zinc ion. This series of HDAC3 selective inhibitors served as tool compounds for investigating the minimal set of HDAC isoforms that must be inhibited for the HIV latency activation in a Jurkat 2C4 cell model and potentially as leads for selective HDAC3 inhibitors for other indications.

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Section: Resultsmentioning

confidence: 99%

“…Because of the high homology of HDAC1 and HDAC2 in the enzyme activation site, selective inhibitors for HDAC1 or HDAC2 have not been developed. Thus, we examined the impact of novel small molecules that inhibit both HDAC1 and HDAC2 (HDAC1/2i) or HDAC3 (HDAC3i) on HIV latency initiation in CD4 T cells (Clausen et al, 2020;Yu et al, 2021). Activated CD4 T cells were infected with HIV-dreGFP/Thy1.2 and cultured for 14d in the presence of each inhibitor, and viral gene expression was measured by flow cytometry (Figure 5A).…”

Section: Hdac1/2 and Hdac3 Play Essential And Distinct Roles In Hiv S...mentioning

confidence: 99%

A histone deacetylase network regulates epigenetic reprogramming and viral silencing in HIV infected cells

Peterson

Lewis

Burgos

et al. 2022

Preprint

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Approximately 70% of the HIV-1 latent reservoir originates from infections of CD4 T cells that occur in the months near the time of ART initiation, raising the possibility that interventions during this period might prevent reservoir seeding and reduce reservoir size. We identify class 1 histone deacetylase inhibitors (HDACi) as potent agents of latency prevention. Inhibiting HDACs in productively infected cells caused extended maintenance of HIV expression and this activity was associated with persistently elevated H3K9 acetylation and reduced H3K9 methylation at the viral LTR promoter region. HDAC inhibition in HIV-infected CD4 T cells during effector-to-memory transition led to striking changes in the memory phenotype of infected cells. Proviral silencing is accomplished through distinct activities of HDAC1/2 and HDAC3. Thus HDACs regulate a critical gateway process for HIV latency establishment and are required for the development of CD4 T-cell memory subsets that preferentially harbor long-lived, latent provirus.

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Development of a selective HDAC inhibitor aimed at reactivating the HIV latent reservoir

Cited by 15 publications

References 20 publications

Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

Discovery of Highly Selective and Potent HDAC3 Inhibitors Based on a 2-Substituted Benzamide Zinc Binding Group

A histone deacetylase network regulates epigenetic reprogramming and viral silencing in HIV infected cells

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