Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1

Crew, Andrew P.; Raina, Kanak; Dong, Hanqing; Qian, Yimin; Wang, Jing; Vigil, Dominico; Serebrenik, Yevgeniy V.; Hamman, Brian D.; Morgan, Alicia; Ferraro, Caterina; Siu, Kam; Neklesa, Taavi K.; Winkler, James D.; Coleman, Kevin; Crews, Craig M.

doi:10.1021/acs.jmedchem.7b00635

Cited by 217 publications

(207 citation statements)

References 29 publications

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“…Compound 3i was recently developed as VHL‐based PROTAC targeting another serine/threonine kinase, TANK‐binding kinase 1 (TBK1), which has been implicated in innate immune response, tumorigenesis, and development. Compound 3i can completely knockdown TBK1 in several cancer cell lines at a concentration of 100 nM, indicating the excellent efficiency of this compound (Figure d) . In addition, VHL‐based PROCTACs have been shown to target transmembrane receptor tyrosine kinases (RTKs) as well as mutants of RTKs …”

Section: All‐small‐molecule Protacs: a Potent And Promising Tool To Ementioning

confidence: 95%

“…Thus, the generation of small‐molecule ligands with high specificity and affinity will remarkably accelerate the development of PROTACs. Second, since PROTACs with different linker lengths exhibit obviously different efficiencies for target degradation, the principles of linker design need to be elucidated. Third, PROTACs with the same ligand for the target protein and different ligands for E3 ubiquitin ligases have variable selectivity for target proteins and efficiencies of target protein degradation .…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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PROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery

et al. 2018

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Proteolysis-targeting chimeric molecules (PROTACs) represent an emerging technique that is receiving much attention for therapeutic intervention. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The hetero-bifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate "undruggable" protein targets, such as transcription factors and non-enzymatic proteins, which are not limited to physiological substrates of the ubiquitin-proteasome system. These findings indicate great prospects for PROTACs in the development of therapeutics. However, there are several limitations related to poor stability, biodistribution, and penetrability in vivo. This review provides an overview of the main PROTAC-based approaches that have been developed and discusses the promising opportunities and considerations for the application of this technology in therapies and drug discovery.

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Section: All‐small‐molecule Protacs: a Potent And Promising Tool To Ementioning

confidence: 95%

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

PROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery

et al. 2018

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“…[ 136 ] Moreover, SGK3‐PROTAC1, which was constructed by the SGK inhibitor 308R and the VHL ligand VH032, was shown to selectively degrade SGK3 at submicromolar concentrations. [ 137 ] Furthermore, other kinases, such as Bruton's tyrosine kinase, [ 138 ] anaplastic lymphoma kinase, [ 139 ] Fms‐like tyrosine kinase 3, [ 140 ] serine/threonine kinase TANK‐binding kinase 1 (TBK1), [ 141 ] CDK6, [ 142 ] and CDK9, [ 143 ] have been designed as effective PROTACs using kinase inhibitors and E3 ligands such as VHL, CRBN, and MDM2, respectively.…”

Section: Strategies For Selective Protein Degradationmentioning

confidence: 99%

Significance of Selective Protein Degradation in the Development of Novel Targeted Drugs and Its Implications in Cancer Therapy

Yang

Wang

Feng

et al. 2020

Advanced Therapeutics

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The evolution of traditional chemotherapeutic drugs to targeted drugs has led to major changes in cancer treatment. However, it remains difficult to develop effective targeted drugs that can act against “undruggable” proteins, including some well‐known oncoproteins such as KRas. Moreover, mutations of target genes limit the use of targeted drugs. Although some strategies such as RNA interference and DNA editing have been adopted to solve these problems, their clinical use remains challenging. Therefore, new strategies are urgently needed to meet the dilemmas encountered in the use of targeted drugs. As protein degradation is a rapid and well‐regulated biological process in cells, targeting protein degradation by inducing cellular protein degradation machinery, regardless of the status of the target, is an attractive idea for developing novel targeted drugs. This review summarizes recent advances in targeted protein degradation, with a focus on the current reagents and strategies used for inducing selective degradation of target proteins to provide clues for the development of novel anticancer drugs and cancer therapies.

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“…Over the past decade, PROTACs have been developed to address an ever-expanding collection of target proteins. Owing to the availability of well-validated chemical matter to repurpose as PROTAC warheads, the majority of early reports focused on degraders of hormone receptors [10][11][12][13], BET-family proteins [14][15][16] and kinases [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. More recently, the applicability of PROTACs has been broadened to include multi-functional proteins (e.g., TRIM24 [34], SMARCA2 [35] tau [36,37]), and HaloTag7-fused proteins for chemical genetics [38].…”

Section: Introductionmentioning

confidence: 99%

“…Our study seeks to do so by modeling the PROTAC's ability to induce formation of the target protein/PROTAC/E3 ligase ternary complex. It has been shown that a PROTAC's ability to bind the target protein is not the primary determinant of whether efficient degradation occurs; rather, it has been suggested that formation of the ternary complex is limiting (i.e., the ability of the PROTAC to simultaneously bind both the target protein and the E3 ligase) [20,22]. It has further been shown that PROTAC selectivity does not necessarily mimic that of its target-binding warhead, but rather depends sensitively on the linker [20,23,24,33]: accordingly, we therefore additionally explore whether the same structure-based modeling can be used to rationalize how and why PROTAC selectivity differs from that of the warhead.…”

Section: Introductionmentioning

confidence: 99%

Rationalizing PROTAC-mediated ternary complex formation using Rosetta

Bai

Kirubakaran

Karanicolas

2020

Preprint

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PROTACs are molecules that combine a target-binding warhead with an E3 ligase-recruiting moiety; by drawing the target protein into a ternary complex with the E3 ligase, PROTACs induce target protein degradation. While PROTACs hold exciting potential as chemical probes and as therapeutic agents, development of a PROTAC typically requires synthesis of numerous analogs to thoroughly explore variations on the chemical linker; without extensive trial and error, it is unclear how to link the two protein-recruiting moieties to promote formation of a productive ternary complex. Here, we describe a structure-based computational method for evaluating suitability of a given linker for ternary complex formation. Our method uses Rosetta to dock the protein components, then builds the PROTAC from its component fragments into each binding mode; complete models of the ternary complex are then refined.We apply this approach to retrospectively evaluate multiple PROTACs from the literature, spanning diverse target proteins. We find that modeling ternary complex formation is sufficient to explain both activity and selectivity reported for these PROTACs, implying that other cellular factors are not key determinants of activity in these cases. We further find that interpreting PROTAC activity is best approached using an ensemble of structures of the ternary complex rather than a single static conformation, and that members of a structurally-conserved protein family can be recruited by the same PROTAC through vastly different binding modes. To encourage adoption of these methods and promote further analyses, we disseminate both the computational methods and the models of ternary complexes. Significance StatementRecent years have brought a flood of interest in developing compounds that selectively degrade protein targets in cells, as exemplified by PROTACs. Fully realizing the promise of PROTACs to transform chemical biology by delivering degraders of diverse and undruggable protein targets has been impeded, however, by the fact that designing a suitable chemical linker between the functional moieties requires extensive trial and error. Here, we describe a structure-based computational method to predict PROTAC activity. We envision that this approach will allow design and optimization of PROTACs for efficient target degradation, selection of E3 ligases best suited for pairing with a given target protein, and understanding the basis by which PROTACs can exhibit different target selectivity than their component warheads.

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Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1

Cited by 217 publications

References 29 publications

PROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery

PROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery

Significance of Selective Protein Degradation in the Development of Novel Targeted Drugs and Its Implications in Cancer Therapy

Rationalizing PROTAC-mediated ternary complex formation using Rosetta

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