Development of a Bestatin-SAHA Hybrid with Dual Inhibitory Activity against APN and HDAC

With five histone deacetylase (HDAC) inhibitors approved for cancer treatment, proteolysis-targeting chimeras (PROTACs) for degradation of HDAC are emerging as an alternative strategy for HDAC-targeted therapeutic intervention. Herein, three bestatin-based hydroxamic acids (P1, P2 and P3) were designed, synthesized and biologically evaluated to see if they could work as HDAC degrader by recruiting cellular inhibitor of apoptosis protein 1 (cIAP1) E3 ubiquitin ligase. Among the three compounds, the bestatin-SAHA hybrid P1 exhibited comparable even more potent inhibitory activity against HDAC1, HDAC6 and HDAC8 relative to the approved HDAC inhibitor SAHA. It is worth noting that although P1 could not lead to intracellular HDAC degradation after 6 h of treatment, it could dramatically decrease the intracellular levels of HDAC1, HDAC6 and HDAC8 after 24 h of treatment. Intriguingly, the similar phenomenon was also observed in the HDAC inhibitor SAHA. Cotreatment with proteasome inhibitor bortezomib could not reverse the HDAC decreasing effects of P1 and SAHA, confirming that their HDAC decreasing effects were not due to protein degradation. Moreover, all three bestatin-based hydroxamic acids P1, P2 and P3 exhibited more potent aminopeptidase N (APN, CD13) inhibitory activities than the approved APN inhibitor bestatin, which translated to their superior anti-angiogenic activities. Taken together, a novel bestatin-SAHA hybrid was developed, which worked as a potent APN and HDAC dual inhibitor instead of a PROTAC.

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GC-MS Investigation and Acetylcholinesterase Inhibitory Activity of Galanthus rizehensis

Zeitschrift für Naturforschung C ◽

10.1515/znc-2013-3-407 ◽

2013 ◽

Vol 68 (3-4) ◽

pp. 118-124 ◽

Cited By ~ 2

Author(s):

Buket Bozkurt Sarikaya ◽

Nehir Unver Somer ◽

Gulen Irem Kaya ◽

Mustafa Ali Onur ◽

Jaume Bastida ◽

...

Keyword(s):

Mass Spectrometry ◽

Gas Chromatography ◽

Inhibitory Activity ◽

Gas Chromatography Mass Spectrometry ◽

Acetylcholinesterase Inhibitory Activity ◽

Aerial Parts ◽

Chromatography Mass Spectrometry ◽

Inhibitory Activities ◽

Alkaloid Extracts ◽

Potent Inhibitory Activity

GC-MS (gas chromatography-mass spectrometry) analyses of alkaloids in the aerial parts and bulbs of Galanthus rizehensis Stern (Amaryllidaceae), collected during two different vegetation periods, was performed. Twenty three alkaloids were identified in four different alkaloid extracts. Acetylcholinesterase (AChE) inhibitory activities of the alkaloid extracts were tested. Both the highest alkaloid diversity and the most potent inhibitory activity (IC50 12.94 μg/ml) were obtained in extracts from the bulbs of G. rizehensis collected during the fruiting period.

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Abstract 4471: Novel PI3K/mTOR dual inhibitor, NVP-BGT226, displays potent inhibitory activity against human head and neck cancer cell growthin vitroandin vivo

10.1158/1538-7445.am10-4471 ◽

2010 ◽

Author(s):

Kwang-Yu Chang ◽

Jang-Yang Chang

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Cancer Cell ◽

Neck Cancer ◽

Inhibitory Activity ◽

Human Head ◽

Dual Inhibitor ◽

Potent Inhibitory Activity

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Histone Deacetylase Inhibitors Reduce Steroidogenesis through SCF-Mediated Ubiquitination and Degradation of Steroidogenic Factor 1 (NR5A1)

Molecular and Cellular Biology ◽

10.1128/mcb.00476-07 ◽

2007 ◽

Vol 27 (20) ◽

pp. 7284-7290 ◽

Cited By ~ 38

Author(s):

Wei-Yi Chen ◽

Jui-Hsia Weng ◽

Chen-Che Huang ◽

Bon-chu Chung

Keyword(s):

Histone Deacetylase ◽

Ubiquitin Ligase ◽

Histone Deacetylase Inhibitors ◽

Trichostatin A ◽

Hdac Inhibitors ◽

E3 Ubiquitin Ligase ◽

Steroidogenic Factor 1 ◽

A Subunit ◽

F Box Protein ◽

Interfering Rna

ABSTRACT Histone deacetylase (HDAC) inhibitors such as trichostatin A and valproic acid modulate transcription of many genes by inhibiting the activities of HDACs, resulting in the remodeling of chromatin. Yet this effect is not universal for all genes. Here we show that HDAC inhibitors suppressed the expression of steroidogenic gene CYP11A1 and decreased steroid secretion by increasing the ubiquitination and degradation of SF-1, a factor important for the transcription of all steroidogenic genes. This was accompanied by increased expression of Ube2D1 and SKP1A, an E2 ubiquitin conjugase and a subunit of the E3 ubiquitin ligase in the Skp1/Cul1/F-box protein (SCF) family, respectively. Reducing SKP1A expression with small interfering RNA resulted in recovery of SF-1 levels, demonstrating that the activity of SCF E3 ubiquitin ligase is required for the SF-1 degradation induced by HDAC inhibitors. Overexpression of exogenous SF-1 restored steroidogenic activities even in the presence of HDAC inhibitors. Thus, increased SF-1 degradation is the cause of the reduction in steroidogenesis caused by HDAC inhibitors. The increased SKP1A expression and SCF-mediated protein degradation could be the mechanism underlying the mode of action of HDAC inhibitors.

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Stabilization of the E3 Ubiquitin Ligase Nrdp1 by the Deubiquitinating Enzyme USP8

Molecular and Cellular Biology ◽

10.1128/mcb.24.17.7748-7757.2004 ◽

2004 ◽

Vol 24 (17) ◽

pp. 7748-7757 ◽

Cited By ~ 112

Author(s):

Xiuli Wu ◽

Lily Yen ◽

Lisa Irwin ◽

Colleen Sweeney ◽

Kermit L. Carraway

Keyword(s):

Ubiquitin Ligase ◽

Tyrosine Kinases ◽

E3 Ubiquitin Ligase ◽

Ring Finger ◽

Growth Factor Receptor ◽

Deubiquitinating Enzyme ◽

Ubiquitin Ligase Activity ◽

Apoptosis Protein ◽

Epidermal Growth ◽

The Stability

ABSTRACT Nrdp1 is a RING finger-containing E3 ubiquitin ligase that physically interacts with and regulates steady-state cellular levels of the ErbB3 and ErbB4 receptor tyrosine kinases and has been implicated in the degradation of the inhibitor-of-apoptosis protein BRUCE. Here we demonstrate that the Nrdp1 protein undergoes efficient proteasome-dependent degradation and that mutations in its RING finger domain that disrupt ubiquitin ligase activity enhance stability. These observations suggest that Nrdp1 self-ubiquitination and stability could play an important role in regulating the activity of this protein. Using affinity chromatography, we identified the deubiquitinating enzyme USP8 (also called Ubpy) as a protein that physically interacts with Nrdp1. Nrdp1 and USP8 could be coimmunoprecipitated, and in transfected cells USP8 specifically bound to Nrdp1 but not cbl, a RING finger E3 ligase involved in ligand-stimulated epidermal growth factor receptor down-regulation. The USP8 rhodanese and catalytic domains mediated Nrdp1 binding. USP8 markedly enhanced the stability of Nrdp1, and a point mutant that disrupts USP8 catalytic activity destabilized endogenous Nrdp1. Our results indicate that Nrdp1 is a specific target for the USP8 deubiquitinating enzyme and are consistent with a model where USP8 augments Nrdp1 activity by mediating its stabilization.

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New structures, chemotaxonomic significance and COX-2 inhibitory activities of cassane-type diterpenoids from the seeds of Caesalpinia minax

RSC Advances ◽

10.1039/c5ra14221k ◽

2015 ◽

Vol 5 (93) ◽

pp. 76567-76574 ◽

Cited By ~ 5

Author(s):

Jian-Long Zhang ◽

Zhi-Hua Chen ◽

Jun Xu ◽

Juan Li ◽

Ya-Fang Tan ◽

...

Keyword(s):

Hydrogen Bonding ◽

Inhibitory Activity ◽

Π Interactions ◽

Inhibitory Activities ◽

Cox 2 ◽

Potent Inhibitory Activity

Eleven new cassane-type diterpenoids, and twelve known compounds were isolated from the seeds of Caesalpinia minax Hance. Some of them displayed potent inhibitory activity against COX-2 through hydrogen bonding and π–π interactions.

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Unexpected Enhancement of HDACs Inhibition by MeS Substitution at C-2 Position of Fluoro Largazole

Marine Drugs ◽

10.3390/md18070344 ◽

2020 ◽

Vol 18 (7) ◽

pp. 344

Author(s):

Bingbing Zhang ◽

Zhu-Wei Ruan ◽

Dongdong Luo ◽

Yueyue Zhu ◽

Tingbo Ding ◽

...

Keyword(s):

Molecular Modeling ◽

Inhibitory Activity ◽

Hdac Inhibitor ◽

Histone Deacetylases ◽

Hdac Inhibitors ◽

Good Tolerance ◽

Glycine Residue ◽

Molecular Modeling Study ◽

Rational Explanation ◽

New Finding

Given our previous finding that fluorination at the C18 position of largazole showed reasonably good tolerance towards inhibitory activity and selectivity of histone deacetylases (HDACs), further modification on the valine residue in the fluoro-largazole’s macrocyclic moiety with S-Me l-Cysteine or Glycine residue was performed. While the Glycine-modified fluoro analog showed poor activity, the S-Me l-Cysteine-modified analog emerged to be a very potent HDAC inhibitor. Unlike all previously reported C2-modified compounds in the largazole family (including our recent fluoro-largazole analogs) where replacement of the Val residue has failed to provide any potency improvement, the S-Me l-Cysteine-modified analog displayed significantly enhanced (five–nine-fold) inhibition of all the tested HDACs while maintaining the selectivity of HDAC1 over HDAC6, as compared to largazole thiol. A molecular modeling study provided rational explanation and structural evidence for the enhanced inhibitory activity. This new finding will aid the design of novel potent HDAC inhibitors.

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Synthesis, molecular modeling, and biological evaluation of quinazoline derivatives containing the 1,3,4-oxadiazole scaffold as novel inhibitors of VEGFR2

RSC Advances ◽

10.1039/c4ra11780h ◽

2015 ◽

Vol 5 (26) ◽

pp. 19914-19923 ◽

Cited By ~ 4

Author(s):

Fang Qiao ◽

Yong Yin ◽

Yu-Ning Shen ◽

She-Feng Wang ◽

Shao Sha ◽

...

Keyword(s):

Molecular Modeling ◽

Inhibitory Activity ◽

Anticancer Agent ◽

Biological Evaluation ◽

Quinazoline Derivatives ◽

Inhibitory Activities ◽

Potent Inhibitory Activity ◽

Mcf 7

A series of 4-alkoxyquinazoline derivatives containing the 1,3,4-oxadiazole scaffold were designed and synthesized. Their inhibitory activities were tested against A549, MCF-7 and Hela. 4j showed the most potent inhibitory activity and may be a potential anticancer agent.

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The complex of TRIP-Br1 and XIAP ubiquitinates and degrades multiple adenylyl cyclase isoforms

eLife ◽

10.7554/elife.28021 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 8

Author(s):

Wenbao Hu ◽

Xiaojie Yu ◽

Zhengzhao Liu ◽

Ying Sun ◽

Xibing Chen ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Feedback Loop ◽

E3 Ubiquitin Ligase ◽

Transcriptional Regulator ◽

Camp Signaling ◽

Inhibitor Of Apoptosis ◽

Biological Processes ◽

Adenylyl Cyclases ◽

Inhibitor Of Apoptosis Protein ◽

Apoptosis Protein

Adenylyl cyclases (ACs) generate cAMP, a second messenger of utmost importance that regulates a vast array of biological processes in all kingdoms of life. However, almost nothing is known about how AC activity is regulated through protein degradation mediated by ubiquitination or other mechanisms. Here, we show that transcriptional regulator interacting with the PHD-bromodomain 1 (TRIP-Br1, Sertad1), a newly identified protein with poorly characterized functions, acts as an adaptor that bridges the interaction of multiple AC isoforms with X-linked inhibitor of apoptosis protein (XIAP), a RING-domain E3 ubiquitin ligase. XIAP ubiquitinates a highly conserved Lys residue in AC isoforms and thereby accelerates the endocytosis and degradation of multiple AC isoforms in human cell lines and mice. XIAP/TRIP-Br1-mediated degradation of ACs forms part of a negative-feedback loop that controls the homeostasis of cAMP signaling in mice. Our findings reveal a previously unrecognized mechanism for degrading multiple AC isoforms and modulating the homeostasis of cAMP signaling.

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Cholinesterase Inhibitory Activities of Selected Halogenated Thiophene Chalcones

Central Nervous System Agents in Medicinal Chemistry ◽

10.2174/1871524918666181119114016 ◽

2019 ◽

Vol 19 (1) ◽

pp. 67-71 ◽

Cited By ~ 3

Author(s):

Della G.T. Parambi ◽

Fakhrya Aljoufi ◽

Vikneswaran Murugaiyah ◽

Githa E. Mathew ◽

Sanal Dev ◽

...

Keyword(s):

Monoamine Oxidase ◽

Inhibitory Activity ◽

Target Therapy ◽

Monoamine Oxidase B ◽

Inhibitory Ability ◽

Ache Inhibitory Activity ◽

Ic50 Values ◽

Inhibitory Activities ◽

Che Inhibitors ◽

Potent Inhibitory Activity

Background: Dual-acting human monoamine oxidase B (hMAO-B) and cholinesterase (ChE) inhibitors are more effective than the classic one-drug one-target therapy for Alzheimer’s disease (AD). Methods: The ChE inhibitory ability of some halogenated thiophene chalcone-based molecules known to be selective hMAO-B inhibitors was evaluated. Results: Based on the IC50 values, the selected compounds were found to moderately inhibit ChE, with IC50 values in the range of 14-70 µM. Among the synthesised molecules, T8 and T6 showed the most potent inhibitory activity against AChE and BChE, respectively. Conclusion: Taken together, the data revealed that T8 could be further optimized to enhance its AChE inhibitory activity.

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