Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations

Wispelaere, Mélissanne de; Du, Guocheng; Donovan, Katherine A.; Zhang, Tinghu; Eleuteri, Nicholas A.; Yuan, Jingting; Kalabathula, Joann; Nowak, Radosław P.; Fischer, Eric S.; Gray, Nathanael S.; Yang, Priscilla L.

doi:10.1038/s41467-019-11429-w

Cited by 137 publications

(111 citation statements)

References 53 publications

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“…These linkers contained ethers with varying numbers of carbons between the oxygens in the repeating unit, which was conveniently indicated via a code (e.g., 2-2-2 indicates 2 carbons between each heteroatom in the chain), and were assembled from the sequential coupling of diverse alkyl halide building blocks. In a representative synthesis (Figure 8), diol (39) was mono O-alkylated with nonsymmetric dihaloalkane (40), then capped with bromide (42). The Gabriel synthesis was then used to install a phthalimide-protected nitrogen to afford 44, and a subsequent protecting group switch gave orthogonally protected linker 45 (coded 6-(2) 5 -6).…”

Section: Current Elements Of Protac Linker Designmentioning

confidence: 99%

Current strategies for the design of PROTAC linkers: a critical review

Troup

Fallan

Baud

2020

Exploration of Targeted Anti-Tumor Therapy

163

162

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PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands; an “anchor” to bind to an E3 ubiquitin ligase and a “warhead” to bind to a protein of interest, connected by a chemical linker. Targeted protein degradation by PROTACs has emerged as a new modality for the knock down of a range of proteins, with the first agents now reaching clinical evaluation. It has become increasingly clear that the length and composition of the linker play critical roles on the physicochemical properties and bioactivity of PROTACs. While linker design has historically received limited attention, the PROTAC field is evolving rapidly and currently undergoing an important shift from synthetically tractable alkyl and polyethylene glycol to more sophisticated functional linkers. This promises to unlock a wealth of novel PROTAC agents with enhanced bioactivity for therapeutic intervention. Here, the authors provide a timely overview of the diverse linker classes in the published literature, along with their underlying design principles and overall influence on the properties and bioactivity of the associated PROTACs. Finally, the authors provide a critical analysis of current strategies for PROTAC assembly. The authors highlight important limitations associated with the traditional “trial and error” approach around linker design and selection, and suggest potential future avenues to further inform rational linker design and accelerate the identification of optimised PROTACs. In particular, the authors believe that advances in computational and structural methods will play an essential role to gain a better understanding of the structure and dynamics of PROTAC ternary complexes, and will be essential to address the current gaps in knowledge associated with PROTAC design.

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Section: Current Elements Of Protac Linker Designmentioning

confidence: 99%

Current strategies for the design of PROTAC linkers: a critical review

Troup

Fallan

Baud

2020

Exploration of Targeted Anti-Tumor Therapy

163

162

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“…The main advantage of the proteolysis strategy is that only a binder is required, and the binder does not need to inhibit the function of the protein. Indeed, unlike classical protein-protein inhibitors or other occupancy-driven inhibitors, the degraders rely on an event-driven mode of action and are consequently often more potent than the parental entity [35][36][37][38][39] . Most of the current degraders target bromodomains or kinase families [40][41][42][43] and only a few target "undruggable" proteins such as transcription factors 44 .…”

mentioning

confidence: 99%

A potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS

2020

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Tumour-associated KRAS mutations are the most prevalent in the three RAS-family isoforms and involve many different amino-acids. Therefore, molecules able to interfere with mutant KRAS protein are potentially important for wide-ranging tumour therapy. We describe the engineering of two RAS degraders based on protein macromolecules (macrodrugs) fused to specific E3 ligases. A KRAS-specific DARPin fused to the VHL E3 ligase is compared to a pan-RAS intracellular single domain antibody (iDAb) fused to the UBOX domain of the CHIP E3 ligase. We demonstrate that while the KRAS-specific DARPin degrader induces specific proteolysis of both mutant and wild type KRAS, it only inhibits proliferation of cancer cells expressing mutant KRAS in vitro and in vivo. Pan-RAS protein degradation, however, affects proliferation irrespective of the RAS mutation. These data show that specific KRAS degradation is an important therapeutic strategy to affect tumours expressing any of the range of KRAS mutations.

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“…However, the application of PROTAC technology for the degradation of foreign proteins (such as viral proteins) remains in its infancy. To date, only the NS3/4A protease degrader DGY-08-097 of HCV has been reported, and its antiviral activity and resistance characteristics are significantly superior to those of the traditional drug telaprevir [ 107 ]. Thus, we propose that the existing 3CL pro inhibitors can be combined with PROTAC technology to develop coronavirus 3CL pro PROTACs.…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

The development of Coronavirus 3C-Like protease (3CLpro) inhibitors from 2010 to 2020

Liu

Liang

Xin

et al. 2020

European Journal of Medicinal Chemistry

129

125

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This review fully describes the coronavirus 3CL pro peptidomimetic inhibitors and nonpeptidic small molecule inhibitors developed from 2010 to 2020. Specifically, the structural characteristics, binding modes and SARs of these 3CL pro inhibitors are expounded in detail by division into two categories: peptidomimetic inhibitors mainly utilize electrophilic warhead groups to covalently bind the 3CL pro Cys145 residue and thereby achieve irreversible inhibition effects, whereas nonpeptidic small molecule inhibitors mainly interact with residues in the S1’, S1, S2 and S4 pockets via hydrogen bonds, hydrophobic bonds and van der Waals forces. Based on the emerging PROTAC technology and the existing 3CL pro inhibitors, 3CL pro PROTAC degraders are hypothesised to be next-generation anti-coronavirus drugs.

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Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations

Cited by 137 publications

References 53 publications

Current strategies for the design of PROTAC linkers: a critical review

Current strategies for the design of PROTAC linkers: a critical review

A potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS

The development of Coronavirus 3C-Like protease (3CLpro) inhibitors from 2010 to 2020

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