Discovery of novel N-hydroxy-2-arylisoindoline-4-carboxamides as potent and selective inhibitors of HDAC11

Martin, Matthew W.; Lee, Jennifer Y.; Lancia, David R.; Ng, Pui Yee; Han, Bingsong; Thomason, Jennifer R.; Lynes, Maureen S.; Marshall, C. Gary; Conti, Chiara; Collis, Alan; Morales, Monica Alvarez; Doshi, Kshama A.; Rudnitskaya, Aleksandra; Yao, Lili; Zheng, Xiaozhang

doi:10.1016/j.bmcl.2018.05.021

Cited by 47 publications

(46 citation statements)

References 13 publications

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“…Moreover, substances which have previously been described as being highly selective HDAC6 inhibitors, with little to no HDAC10 activity (e.g. tubastatin A (8), HPOB (16), nexturastat (17)) have also been found to be good HDAC10 binders. We investigated SAR surrounding the indole-fused ring of 8, and found a strong dependency for HDAC10 binding on the presence of an appropriately placed basic amine functionality.…”

Section: Discussionmentioning

confidence: 99%

“…3 Far fewer selective inhibitors of the Class IIA, HDAC10 or HDAC11 subtypes have been reported. [13][14][15][16][17] In 2003, tubacin (7) was described as the first selective HDAC6 inhibitor (Figure 1). 18 In the intervening years, many additional HDAC6 inhibitors with good selectivity profiles have been described, the most well-known (besides tubacin) being tubastatin A (8).…”

Section: Introductionmentioning

confidence: 99%

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Selective Inhibition of Histone Deacetylase 10: Hydrogen Bonding to the Gatekeeper Residue is Implicated

Géraldy¹,

Morgen²,

Sehr

et al. 2019

J. Med. Chem.

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The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as drug targets. The isozyme HDAC10 contributes to chemotherapy resistance and has recently been described to be a polyamine deacetylase, but no studies toward selective HDAC10 inhibitors have been published. Using two complementary assays, we found Tubastatin A, an HDAC6 inhibitor, to potently bind HDAC10. We synthesized Tubastatin A derivatives and found that a basic amine in the cap group was required for strong HDAC10 binding. HDAC10 inhibitors mimicked knockdown by causing dose-dependent accumulation of acidic vesicles in a neuroblastoma cell line. Furthermore, docking into human HDAC10 homology models indicated that a hydrogen bond between a cap group nitrogen and the gatekeeper residue Glu272 was responsible for potent HDAC10 binding. Taken together, our data provide an optimal platform for the development of HDAC10-selective inhibitors, as exemplified with the Tubastatin A scaffold.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Selective Inhibition of Histone Deacetylase 10: Hydrogen Bonding to the Gatekeeper Residue is Implicated

Géraldy¹,

Morgen²,

Sehr

et al. 2019

J. Med. Chem.

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“…www.nature.com/scientificreports www.nature.com/scientificreports/ The HDAC11 inhibitors presented here are novel and highly selective. They have low IC 50 values against HDAC11 activity 33 . At the same time, their ADME properties need to be further optimized for conducting in vivo experiments.…”

Section: Discussionmentioning

confidence: 99%

“…Similar reduction was also observed in the levels of HK2, PDK1 and PDK2 Selective HDAC11 inhibitors reduced stem-like properties of CSCs. To further investigate inhibition of HDAC11, we utilized highly selective and potent inhibitors of HDAC11 those were developed by FORMA Therapeutics 33,34 . We focused on two of these inhibitors FT234 and FT895 (Fig.…”

Section: Depletion Of Hdac11 Ablates Downstream Targets and Abrogatesmentioning

confidence: 99%

Novel HDAC11 inhibitors suppress lung adenocarcinoma stem cell self-renewal and overcome drug resistance by suppressing Sox2

Bora-Singhal

Mohankumar

Saha

et al. 2020

Sci Rep

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Non-small cell lung cancer (NSCLC) is known to have poor patient outcomes due to development of resistance to chemotherapy agents and the EGFR inhibitors, which results in recurrence of highly aggressive lung tumors. Even with recent success in immunotherapy using the checkpoint inhibitors, additional investigations are essential to identify novel therapeutic strategies for efficacious treatment for NSCLC. Our finding that high levels of histone deacetylase 11 (HDAC11) in human lung tumor tissues correlate with poor patient outcome and that depletion or inhibition of HDAC11 not only significantly reduces self-renewal of cancer stem cells (CSCs) from NSCLC but also decreases Sox2 expression that is essential for maintenance of CSCs, indicates that HDAC11 is a potential target to combat NSCLC. We find that HDAC11 suppresses Sox2 expression through the mediation of Gli1, the Hedgehog pathway transcription factor. In addition, we have used highly selective HDAC11 inhibitors that not only target stemness and adherence independent growth of lung cancer cells but these inhibitors could also efficiently ablate the growth of drug-insensitive stem-like cells as well as therapy resistant lung cancer cells. These inhibitors were found to be efficacious even in presence of cancer associated fibroblasts which have been shown to contribute in therapy resistance. Our study presents a novel role of HDAC11 in lung adenocarcinoma progression and the potential use of highly selective inhibitors of HDAC11 in combating lung cancers. Lung cancer is the leading cause of cancer related mortality in the US, with about 234,000 new cases expected to be diagnosed in 2018 and 154,000 deaths 1. Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer and has notably poor survival rates 2. Early stage NSCLC is treated by surgical resection, radiotherapy or chemotherapy. Chemotherapeutic agents like gemcitabine, platinum compounds and taxanes are widely used to treat both lung adenocarcinomas as well as squamous cell carcinomas, but the success rates vary significantly 3. NSCLC in smokers generally harbor mutations in the KRAS oncogene, while mutations in EGFR gene are prevalent in NSCLC in non-smokers. NSCLC has high mutational burden, and hence immunotherapy using checkpoint inhibitors is highly beneficial to a subset of the patients 4,5. Nevertheless, a significant number of NSCLC patients do not respond to immunotherapy; hence it is imperative to identify novel therapeutic strategies to combat this disease. This notion is further strengthened by the fact that there are no effective drugs that can target KRAS mutant lung cancers; furthermore, while there are highly potent tyrosine kinase inhibitors that target mutant EGFR, patients invariably develop resistance to these inhibitors resulting in recurrence of highly drug resistant metastatic tumors 6,7. It has been proposed that cancer stem cells (CSCs) contribute to tumor initiation, dormancy, recurrence and metastasis of various tumors, including NSCLC 8,9. It has been suggested ...

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“…This broad target range has been suggested to be the source of unwanted side effects 49 and hence an increasing number of subtype selective HDAC inhibitors has been developed as chemical tools and drug candidates. [50][51][52] (reviewed in 53 ) Suitable assay systems must be available to enable the development of isozyme-selective HDAC inhibitors, but certain isozymes currently lack a facile activity assay. Specifically, due to the newly discovered substrate specificity of HDAC10, the standard HDAC activity assay based on the hydrolysis of an acetyllysine substrate is inappropriate.…”

Section: Figure 2: Structures Of Selected Hdac Inhibitorsmentioning

confidence: 99%

First Fluorescent Acetylspermidine Deacetylation Assay for HDAC10 Identifies Inhibitors of Neuroblastoma Cell Colony Growth That Increase Lysosome Accumulation

Herp¹,

Ridinger²,

Robaa³

et al. 2020

Preprint

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Histone deacetylases (HDACs) are important epigenetic regulators involved in many diseases, esp. cancer. First HDAC inhibitors have been approved for anticancer therapy and many are in clinical trials. Among the 11 zinc-dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement e.g. in the pathogenesis of neuroblastoma. This is due in part to a lack of robust enzymatic conversion assays. In contrast to the protein lysine deacetylase and deacylase activity of the other HDAC subtypes, it has recently been shown that HDAC10 has strong preferences for deacetylation of oligoamine substrates like spermine or spermidine. Hence, it also termed a polyamine deacetylase (PDAC). Here, we present the first fluorescent enzymatic conversion assay for HDAC10 using an aminocoumarin labelled acetyl spermidine derivative to measure its PDAC activity, which is suitable for high-throughput screening. Using this assay, we identified potent inhibitors of HDAC10 mediated spermidine deacetylation in-vitro. Among those are potent inhibitors of neuroblastoma colony growth in culture that show accumulation of lysosomes, implicating disturbance of autophagic flux.

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Discovery of novel N-hydroxy-2-arylisoindoline-4-carboxamides as potent and selective inhibitors of HDAC11

Cited by 47 publications

References 13 publications

Selective Inhibition of Histone Deacetylase 10: Hydrogen Bonding to the Gatekeeper Residue is Implicated

Selective Inhibition of Histone Deacetylase 10: Hydrogen Bonding to the Gatekeeper Residue is Implicated

Novel HDAC11 inhibitors suppress lung adenocarcinoma stem cell self-renewal and overcome drug resistance by suppressing Sox2

First Fluorescent Acetylspermidine Deacetylation Assay for HDAC10 Identifies Inhibitors of Neuroblastoma Cell Colony Growth That Increase Lysosome Accumulation

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