Efficient protein knockdown of HaloTag-fused proteins using hybrid molecules consisting of IAP antagonist and HaloTag ligand

Tomoshige, Shusuke; Hashimoto, Yuichi; Ishikawa, Minoru

doi:10.1016/j.bmc.2016.05.035

Cited by 40 publications

(39 citation statements)

References 31 publications

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“…To apply the protein knockdown technology to BCR-ABL degradation, we designed and developed a hybrid molecule, SNIPER(ABL)-2 (Table 1) by conjugating MeBS to imatinib as a ligand for BCR-ABL. 25) As expected, SNIPER(ABL)-2 induced degradation of BCR-ABL protein at 30-100 µM. BCR-ABL is a constitutively active tyrosine kinase and drives uncontrolled cellular proliferation through signaling pathways that involve the STAT5 and CrkL.…”

Section: Development Of a Potent Degrader Against Bcr-abl Sniper(abl)supporting

confidence: 60%

Development of a Potent Protein Degrader against Oncogenic BCR-ABL Protein

et al. 2019

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Chromosomal translocation occurs in some cancer cells, resulting in the expression of aberrant oncogenic fusion proteins that include BCR-ABL in chronic myelogenous leukemia (CML). Inhibitors of ABL tyrosine kinase, such as imatinib and dasatinib, exhibit remarkable therapeutic effects, although emergence of drug resistance hampers the therapy during long-term treatment. An alternative approach to treat CML is to downregulate expression of the BCR-ABL protein. Recently, we have devised a protein knockdown system by hybrid molecules named Specific and Nongenetic inhibitor of apoptosis protein [IAP]-dependentProtein Erasers (SNIPER). This system is designed to induce IAP-mediated ubiquitylation and proteasomal degradation of target proteins. In this review, we describe the development of SNIPER against BCR-ABL, and discuss the features and prospect for treatment of CML.

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Section: Development Of a Potent Degrader Against Bcr-abl Sniper(abl)supporting

confidence: 60%

Development of a Potent Protein Degrader against Oncogenic BCR-ABL Protein

et al. 2019

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“…Ligand optimization of the cIAP1 recruiting moiety bestatin has reduced cIAP1 autoubiquitination (Itoh et al, 2011a), but their efficacy remained in the micromolar range. Thus far, SNIPERs have successfully degraded multiple cellular targets, e.g., Cellular Retinoic Acid-Binding Protein I (CRABPI) and CRABPII (Itoh et al, 2010; Itoh et al, 2012; Okuhira et al, 2017), ERα (Itoh et al, 2011b; Demizu et al, 2012; Okuhira et al, 2013), the spindle regulatory protein Transforming Acidic Coiled-Coil-3 (TACC3) (Ohoka et al, 2014), the Breakpoint Cluster Region-Abelson tyrosine kinase (BCR-ABL) (Demizu et al, 2016) and various HaloTag fusion proteins (Tomoshige et al, 2016). Recently, the introduction of the IAP antagonist LCL161 has boosted SNIPER activity to the low nanomolar range, and allowed SNIPER evaluation in mouse xenograft models for the first time (Ohoka et al, 2017).…”

Section: Targeted Proteasomal Degradationmentioning

confidence: 99%

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Cromm

Crews

2017

Cell Chemical Biology

314

261

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Traditional pharmaceutical drug discovery is almost exclusively focused on directly controlling protein activity to cure diseases. Modulators of protein activity, especially inhibitors, are developed and applied at high concentration to achieve maximal effects. Thereby, reduced bioavailability and off-target effects can hamper compound efficacy. Nucleic acid-based strategies that control protein function by affecting expression have emerged as an alternative. However, metabolic stability and broad bioavailability represent development hurdles that remain to be overcome for these approaches. More recently, utilizing the cell’s own protein destruction machinery for selective degradation of essential drivers of human disorders has opened up a new and exciting area of drug discovery. Small molecule-induced proteolysis of selected substrates offers the potential of reaching beyond the limitations of the current pharmaceutical paradigm to expand the druggable target space.

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“…Researchers have demonstrated that, similar to standard PROTAC technology, the composition of the E3 ligase binder, the linker attachment point, and linker length were important factors affecting degradation efficiency. This technology was applied to degrade a range of targets, including GFP, ERK1, MEK1, TNFα, Cdc42, CREB1 and c‐Jun, demonstrating the generality of the approach . As plasmids containing HaloTag fused with 20 000 human genes are commercially available, this technology should be applicable to study the degradation of numerous proteins, regardless of whether known binders/inhibitors exist.…”

Section: Covalent Inducers Of Protein Degradationmentioning

confidence: 99%

“…HaloPROTACs are another type of small molecule degrader, relying solely on a covalent mode of action with a HaloTag fusion domain (Figure E) . HaloTag is a modified bacterial dehalogenase enzyme which covalently binds to a chlorohexyl chain through its Asp106 moiety, and has been widely used in the literature to covalently label proteins in vivo .…”

Section: Covalent Inducers Of Protein Degradationmentioning

confidence: 99%

“…HaloTag is a modified bacterial dehalogenase enzyme which covalently binds to a chlorohexyl chain through its Asp106 moiety, and has been widely used in the literature to covalently label proteins in vivo . Two research groups initially developed HaloTag‐binding degradation inducers by attaching the chlorohexyl group to small molecule VHL and IAP binders (probes 17 and 18 , 19 respectively, Figure ). In cells, these HaloPROTACs covalently bound to the HaloTag fusion protein, and recruited the desired E3 ligase to facilitate ubiquitin transfer, leading to subsequent degradation by the proteasome.…”

Section: Covalent Inducers Of Protein Degradationmentioning

confidence: 99%

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