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

Okuhira, Keiichiro; Ohoka, Nobumichi; Sai, Kimie; Nishimaki-Mogami, Tomoko; Itoh, Yukihiro; Ishikawa, Minoru; Hashimoto, Yuichi; Naito, Mikihiko

doi:10.1016/j.febslet.2011.03.019

Cited by 105 publications

(101 citation statements)

References 18 publications

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“…43 Furthermore, this hydroxyproline derivatives were further used for the synthesis of HaloPROTACs to target HaloTag7 fusion proteins, by developing chloroalkane-containing PROTACs against Halo Tag7 fusion protein using the acyl amine moiety for recognizing VHL. [53][54][55] They recruited a class of bestatin ester analogues (MeBS, methyl bestatin), a ligand binding to the baculoviral IAP repeat domains of cIAP1, to all-trans retinoid acid to target CRABP-I and II (cellular retinoic acid binding proteins-I and II). BRD4 inhibitors have been extendedly studied and shown promises in anticancer therapy against MYC-driven malignancies.…”

Section: Small Molecule-based Protacmentioning

confidence: 99%

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The PROTAC technology in drug development

Zou

Wang

2019

Cell Biochemistry & Function

201

135

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Currently, a new technology termed PROTAC, proteolysis targeting chimera, has been developed for inducing the protein degradation by a targeting molecule. This technology takes advantage of a moiety of targeted protein and a moiety of recognizing E3 ubiquitin ligase and produces a hybrid molecule to specifically knock down a targeted protein. During the first decade, three pedigreed groups worked on the development of this technology. To date, this technology has been extended by different groups, aiming to develop new drugs against different diseases including cancers. This review summarizes the contributions of the groups for the development of PROTAC. Significance of the study This review summarized the development of the PROTAC technology for readers and also presented the author's opinions on the application of the technology in tumor therapy.

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Section: Small Molecule-based Protacmentioning

confidence: 99%

“…44 Many of the small molecule-based PROTACs have been developed intensively to target the BET family proteins. 55 Thus, the cIAP-1-based PROTAC could be able to induce the ubiquitination and degradation of the intracellular CRABP-I/II proteins. The first effort was to link BET inhibitor JQ1 to a moiety of VHL.…”

Section: Small Molecule-based Protacmentioning

confidence: 99%

The PROTAC technology in drug development

Zou

Wang

2019

Cell Biochemistry & Function

201

135

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“…5 Recently, the Hashimoto lab has successfully used bestatin to recruit cIAP1 to degrade CRABPs in cells. 14-17 However, bestatin is commonly used as an aminopeptidase inhibitor, which can lead to off-target effects. 18 Furthermore, ligands for IAPs often induce degradation of the E3 ligase itself, 19, 20 , (an effect observed with some bestatin hybrids) 16 that complicates their use in PROTACs.…”

Section: Introductionmentioning

confidence: 99%

HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins

Buckley¹,

Raina²,

et al. 2015

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Small molecule-induced protein degradation is an attractive strategy for the development of chemical probes. One method for inducing targeted protein degradation involves the use of PROTACs, heterobifunctional molecules that can recruit specific E3 ligases to a desired protein of interest. PROTACs have been successfully used to degrade numerous proteins in cells, but the peptidic E3 ligase ligands used in previous PROTACs have hindered their development into more mature chemical probes or therapeutics. We report the design of a novel class of PROTACs that incorporate small molecule VHL ligands to successfully degrade HaloTag7 fusion proteins. These HaloPROTACs will inspire the development of future PROTACs with more drug-like properties. Additionally, these HaloPROTACs are useful chemical genetic tools, due to their ability to chemically knockdown widely used HaloTag7 fusion proteins in a general fashion.

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“…2c), through the use of the ligand bestatin. cIAP1 based PROTACs have been used to selectively degrade a number of proteins, such as CRABP-II[25], ERα[26,27], and TACC3[28]. Unfortunately, these bestatin-based PROTACs, like the parent ligand[29], induced autoubiquitination and degradation of the E3 ligase itself, a potential explanation for their relatively low potency.…”

Section: Mdm2 and Iapmentioning

confidence: 99%

Targeted protein knockdown using small molecule degraders

Raina

Crews

2017

Current Opinion in Chemical Biology

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Small molecule probes of biological systems have traditionally been designed to bind to and inhibit the active sites of their protein targets. While this class of pharmacological agents has been broadened by the development of a small number of allosteric and protein-protein interaction (PPI) inhibitors, conventional drug design still excludes ‘undruggable’ proteins that are neither enzymes nor receptors. Recent years have seen the emergence of new classes of small molecules that can target hitherto undruggable proteins by recruiting the cellular proteostasis machinery to selectively tag them for degradation. These molecules, especially the class known as Proteolysis Targeting Chimera (PROTACs), represent a paradigm shift in chemical genetics, but their most tantalizing potential is as novel therapeutic agents. This review briefly summarizes the preclinical development of small molecule-based protein degraders, and describes the recent improvements in the technology that have positioned PROTACs on the cusp of entering the clinic.

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

Cited by 105 publications

References 18 publications

The PROTAC technology in drug development

The PROTAC technology in drug development

HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins

Targeted protein knockdown using small molecule degraders

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