Degradation-promoters of cellular inhibitor of apoptosis protein 1 based on bestatin and actinonin

Sato, Shinichi; Tetsuhashi, Masashi; Sekine, Keiko; Miyachi, Hiroyuki; Naito, Mikihiko; Hashimoto, Yuichi; Aoyama, Hiroshi

doi:10.1016/j.bmc.2008.02.024

Cited by 25 publications

(9 citation statements)

References 51 publications

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“…[31] However,t his new class of small-molecule PROTACs has several key limitations.N otably,n umerous off-target effects were observed, which were attributed to the bestatin moiety,acommon aminopeptidase inhibitor. [32] In addition, it was shown that high concentrations are needed to effectively degrade targeted proteins. [31] Finally,the IAP ligands used are known to often induce IAP autoubiquitination and degradation, which could be ac oncern for their use in therapeutic PROTACs.…”

Section: Recruiting the E3 Ubiquitin Ligase Clap1mentioning

confidence: 99%

Small‐Molecule PROTACS: New Approaches to Protein Degradation

2016

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The current inhibitor-based approach to therapeutics has inherent limitations owing to its occupancy-based model: 1) there is a need to maintain high systemic exposure to ensure sufficient in vivo inhibition, 2) high in vivo concentrations bring potential for off-target side effects, and 3) there is a need to bind to an active site, thus limiting the drug target space. As an alternative, induced protein degradation lacks these limitations. Based on an event-driven model, this approach offers a novel catalytic mechanism to irreversibly inhibit protein function by targeting protein destruction through recruitment to the cellular quality control machinery. Prior protein degrading strategies have lacked therapeutic potential. However, recent reports of small-molecule-based proteolysis-targeting chimeras (PROTACs) have demonstrated that this technology can effectively decrease the cellular levels of several protein classes.

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Section: Recruiting the E3 Ubiquitin Ligase Clap1mentioning

confidence: 99%

Small‐Molecule PROTACS: New Approaches to Protein Degradation

2016

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“…We previously reported that a class of small molecules, represented by (−)‐ N ‐[(2 S ,3 R )‐3‐amino‐2‐hydroxy‐4‐phenyl‐butyryl]‐ l ‐leucine methyl ester (MeBS), destabilize cellular inhibitor of apoptosis protein 1 (cIAP1), a ubiquitin‐ligase (E3) belonging to IAP (inhibitor of apoptosis protein) family [10–12], and sensitize cancer cells to apoptosis induced by anti‐cancer drugs and death receptor ligation [13–16]. MeBS directly interacts with cIAP1 at its BIR3 domain and induces auto‐ubiquitylation of cIAP1 depending on its RING domain, resulting in the proteasomal degradation of cIAP1.…”

Section: Introductionmentioning

confidence: 99%

Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein

Okuhira¹,

Ohoka²,

Sai³

et al. 2011

FEBS Letters

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105

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Edited by Noboru MizushimaKeywords: Cellular inhibitor of apoptosis protein 1 Cellular retinoic acid binding protein-II Protein knockdown Ubiquitin Proteasome a b s t r a c t Manipulation of protein stability with small molecules is a challenge in the field of drug discovery. Here we show that cellular retinoic acid binding protein-II (CRABP-II) can be specifically degraded by a novel compound, SNIPER-4, consisting of (À)-N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine methyl ester and all-trans retinoic acid that are ligands for cellular inhibitor of apoptosis protein 1 (cIAP1) and CRABP-II, respectively. Mechanistic analysis revealed that SNIPER-4 induces cIAP1-mediated ubiquitylation of CRABP-II, resulting in the proteasomal degradation. The protein knockdown strategy employing the structure of SNIPER-4 could be applicable to other target proteins.

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“…Mutational and deletion studies of key BIR3 binding pocket residues of XIAP, cIAP1 and cIAP2 provide evidence that these compounds interact directly with the BIR3 domain of cIAP1 but not the other IAPs. FP assays, photoaffinity labeling and SPR (Surface Plasmon Resonance) experiments with these IAP proteins have supported this conclusion [166][167][168]. Unfortunately no data has been published on the mode of binding of these compounds to the BIR3 domain of cIAP1.…”

Section: Iap Inhibitors Not Derived From the Avpx Leadmentioning

confidence: 57%

Targeting IAPs as An Approach to Anti-Cancer Therapy

Straub¹

2011

CTMC

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Apoptosis is an essential process for embryonic and lymphocyte development, immune system modulation and tissue homeostasis. Defects in apoptotic signaling often lead to diseases of immune deficiency, neurodegeneration and cancer [1, 2]. In the cancer arena, these defects may contribute to the establishment and growth of tumors. Moreover, many cytotoxic chemotherapies act in part by activating these apoptotic networks. Occasionally apoptotic pathways are activated, however key players downstream of initiation are inhibited by negative regulators that have been dysregulated by the diseased state of the cell. Removal of these barriers to apoptosis signaling, it has been rationalized, could restore cell death in diseased cells while sparing those that are not primed for programmed cell death. Additionally, the subversion of these death evading mechanisms may re-sensitize cells that have developed resistance to chemotherapies in this manner. The importance of apoptosis as a maintenance process, and the promise that restoring this signaling could mean in treating cancer has placed many targets on the front line of oncology research. Approaches are being developed that will activate death receptor pathways, synthetically activate caspases, restore the activity of tumor suppressor genes such as p53, and counteract the effects of anti-apoptotic factors. Among these approaches, small molecules are in clinical trials against several anti-apoptotic players, namely the Bcl-2 and IAP proteins. This review will focus on the efforts being advanced against the Inhibitor of Apoptosis Proteins (IAP), the chemical matter of the inhibitors and the biology emerging from this research.

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Degradation-promoters of cellular inhibitor of apoptosis protein 1 based on bestatin and actinonin

Cited by 25 publications

References 51 publications

Small‐Molecule PROTACS: New Approaches to Protein Degradation

Small‐Molecule PROTACS: New Approaches to Protein Degradation

Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein

Targeting IAPs as An Approach to Anti-Cancer Therapy

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