Characterization of Conformationally Constrained Benzanilide Scaffolds for Potent and Selective HDAC8 Targeting

Hassan, Muhammad Murtaza; Israelian, Johan; Nawar, Nabanita; Ganda, Giovanni; Manaswiyoungkul, Pimyupa; Raouf, Yasir S.; Armstrong, David R.; Sedighi, Abootaleb; Olaoye, Olasunkanmi O.; Erdogan, Fettah; Cabral, Aaron D.; Angeles, Fabrizio; Altintas, Rabia; Araujo, Elvin D. de; Gunning, Patrick T.

doi:10.1021/acs.jmedchem.0c01025

Cited by 28 publications

(48 citation statements)

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“…Phenotypic Screening of HDAC8 inhibitors against S. mansoni . Phenotypic screening against S. mansoni was conducted using a previously published library of HDAC8‐targeting small molecule inhibitors [31] of varying potency and selectivity, as well as PCI34051 , a known HDAC8‐selective inhibitor (Figure 2, 3, S1, S2, Table 1, 2, S1). Single concentration viability screens were performed against newly transformed schistosomula (NTS) at 10 μM with a 72 h incubation time.…”

Section: Resultsmentioning

confidence: 99%

“… The top HDAC8 selective inhibitors (>10‐fold selective) with an HDAC8 IC 50 >100 nM. The previously reported [31] HDAC8 IC 50 (Electrophoretic Mobility Shift Assay‐EMSA) values and selectivity index (SI) are listed below and the inhibitors are arranged in a decreasing order of hHDAC8 selectivity (left to right) over human HDACs 3, 6, and 11.…”

Section: Resultsmentioning

confidence: 99%

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Phenotypic Screening of Histone Deacetylase (HDAC) Inhibitors against Schistosoma mansoni

et al. 2022

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Schistosomiasis is a prevalent yet neglected tropical parasitic disease caused by the Schistosoma genus of blood flukes. Praziquantel is the only currently available treatment, hence drug resistance poses a major threat. Recently, histone deacetylase 8 (HDAC8) selective inhibitors have been proposed as a viable treatment for schistosomiasis. Herein, we report the phenotypic screening of a focused library of small molecules of varying HDAC isozyme-inhibition profiles, including eight HDAC8 inhibitors with > 10-fold selectivity in comparable functional inhibition assays and IC 50 values against HDAC8 < 100 nM. HDAC8-selective inhibitors showed the lowest potency against Schistosoma mansoni newly transformed schistosomula (NTS). Pan-HDAC inhibitors MMH258, MMH259, and MMH373, as assessed by functional inhibition assays, with minimal or noobserved hHDAC8 and SmHDAC8 activities, were active against both NTS (MMH258, IC 50 = 1.5 μM; MMH259, IC 50 = 2.3 μM) and adult S. mansoni (MMH258, IC 50 = 2.1 μM; MMH373, IC 50 = 3.4 μM). Our results indicate that neither hHDAC8 nor SmHDAC8 activity were directly correlated to their NTS and adult S. mansoni activities.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Phenotypic Screening of Histone Deacetylase (HDAC) Inhibitors against Schistosoma mansoni

et al. 2022

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“…Both PCI-34051 (120-fold selective for HDAC8) and MMH-410 (15-fold selective for HDAC8) exhibited nanomolar HDAC8 potency but no observable activity in MV4-11 and MRC9 cells (Table S5). , Given the established pathogenetic role of HDAC modulation in AML and PTCL, cell lines representing these disease types were used to profile the library and investigate the cellular pharmacology of KT-531.…”

Section: Discussionmentioning

confidence: 99%

Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia

et al. 2021

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Epigenetic targeting has emerged as an efficacious therapy for hematological cancers. The rare and incurable T-cell prolymphocytic leukemia (T-PLL) is known for its aggressive clinical course. Current epigenetic agents such as histone deacetylase (HDAC) inhibitors are increasingly used for targeted therapy. Through a structure–activity relationship (SAR) study, we developed an HDAC6 inhibitor KT-531, which exhibited higher potency in T-PLL compared to other hematological cancers. KT-531 displayed strong HDAC6 inhibitory potency and selectivity, on-target biological activity, and a safe therapeutic window in nontransformed cell lines. In primary T-PLL patient cells, where HDAC6 was found to be overexpressed, KT-531 exhibited strong biological responses, and safety in healthy donor samples. Notably, combination studies in T-PLL patient samples demonstrated KT-531 synergizes with approved cancer drugs, bendamustine, idasanutlin, and venetoclax. Our work suggests HDAC inhibition in T-PLL could afford sufficient therapeutic windows to achieve durable remission either as stand-alone or in combination with targeted drugs.

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“…Confirmationally constrained phenylhydroxamic acids as selective HDAC8 inhibitors were described, culminating in an HDAC8 inhibitor having HDAC8 IC 50 = 23 n m and up to 410‐fold selectivity over HDAC3, 6, and 11 [112]. Synergistic toxicity between poly(ADP‐ribose) polymerase inhibitors and HDACis has been reported in preclinical models of triple‐negative breast cancer, prostate, and ovarian cancer [113].…”

Section: Successful Medicinal Chemistry Approaches and Clinical Trans...mentioning

confidence: 99%

Therapeutic targeting of chromatin: status and opportunities

Siklos

Kubicek

2021

The FEBS Journal

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The molecular characterization of mechanisms underlying transcriptional control and epigenetic inheritance since the 1990s has paved the way for the development of targeted therapies that modulate these pathways. In the past two decades, cancer genome sequencing approaches have uncovered a plethora of mutations in chromatin modifying enzymes across tumor types, and systematic genetic screens have identified many of these proteins as specific vulnerabilities in certain cancers. Now is the time when many of these basic and translational efforts start to bear fruit and more and more chromatin‐targeting drugs are entering the clinic. At the same time, novel pharmacological approaches harbor the potential to modulate chromatin in unprecedented fashion, thus generating entirely novel opportunities. Here, we review the current status of chromatin targets in oncology and describe a vision for the epigenome‐modulating drugs of the future.

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Characterization of Conformationally Constrained Benzanilide Scaffolds for Potent and Selective HDAC8 Targeting

Cited by 28 publications

References 50 publications

Phenotypic Screening of Histone Deacetylase (HDAC) Inhibitors against Schistosoma mansoni

Phenotypic Screening of Histone Deacetylase (HDAC) Inhibitors against Schistosoma mansoni

Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia

Therapeutic targeting of chromatin: status and opportunities

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