Solid-phase synthesis for thalidomide-based proteolysis-targeting chimeras (PROTAC)

Krajčovičová, Soňa; Jorda, Radek; Hendrychová, Denisa; Kryštof, Vladimír; Soural, Miroslav

doi:10.1039/c8cc08716d

Cited by 43 publications

(47 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is made The copyright holder for this preprint this version posted December 17, 2020. ; https://doi.org/10.1101/2020.12.16.423097 doi: bioRxiv preprint where both the neoantigen is known and it possesses an available degrader. Although currently there are only a few dozen commercially available degraders of protein targets, large-scale efforts at converting protein inhibitors to degraders in a modular fashion (47), as well as target agnostic degrader technologies (48), may bring such a treatment strategy within reach in the near future.…”

Section: Discussionmentioning

confidence: 99%

Sensitive and quantitative detection of MHC-I displayed neoepitopes using a semi-automated workflow and TOMAHAQ mass spectrometry

Pollock¹,

Rose²,

Darwish³

et al. 2020

Preprint

View full text Add to dashboard Cite

Advances in several key technologies, including MHC peptidomics, has helped fuel our understanding of basic immune regulatory mechanisms and identify T cell receptor targets for the development of immunotherapeutics. Isolating and accurately quantifying MHC-bound peptides from cells and tissues enables characterization of dynamic changes in the ligandome due to cellular perturbations. This multi-step analytical process remains challenging, and throughput and reproducibility are paramount for rapidly characterizing multiple conditions in parallel. Here, we describe a robust and quantitative method whereby peptides derived from MHC-I complexes from a variety of cell lines, including challenging adherent lines, can be enriched in a semi-automated fashion on reusable, dry-storage, customized antibody cartridges. TOMAHAQ, a targeted mass spectrometry technique that combines sample multiplexing and high sensitivity, was employed to characterize neoepitopes displayed on MHC-I by tumor cells and to quantitatively assess the influence of neoantigen expression and induced degradation on neoepitope presentation.

show abstract

Section: Discussionmentioning

confidence: 99%

Sensitive and quantitative detection of MHC-I displayed neoepitopes using a semi-automated workflow and TOMAHAQ mass spectrometry

Pollock¹,

Rose²,

Darwish³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…[ 59 ] Recently, four NRTKs were targeted using the PROTAC technology: the Janus kinases (JAKs), [ 60 ] the breakpoint cluster region‐Abelson (BCR‐ABL), [ 61,62 ] the focal adhesion kinase (FAK), [ 63–65 ] and the Bruton's tyrosine kinase (BTK). [ 66–72 ]…”

Section: Nonreceptor Tyrosine Kinase (Nrtk) Degradersmentioning

confidence: 99%

“…have developed a new methodology to rapidly synthesized CRBN‐based PROTACs and took as a proof of concept for their method, the synthesis of several BTK‐PROTACs. [ 72 ] This method consists of a preloaded resin with a thalidomide moiety and a small PEG linker which could be further acetylated to increase its length. Finally, several commercially available protein kinase inhibitors were introduced on the linker.…”

Section: Nonreceptor Tyrosine Kinase (Nrtk) Degradersmentioning

confidence: 99%

“…An 85% BTK knockdown was achieved at a concentration of 2 × 10 −6 m . [ 72 ] With this new development tool in hands, the time production of CRBN‐based PROTACs could considerably decrease and permit more rapid preliminary screening. This kind of tool for the synthesis of cIAP‐, VHL‐, and MDM2‐based PROTAC could enhance the time production of other categories of PROTACs.…”

Section: Nonreceptor Tyrosine Kinase (Nrtk) Degradersmentioning

confidence: 99%

See 1 more Smart Citation

PROteolysis TArgetting Chimeras (PROTACs) Strategy Applied to Kinases: Recent Advances

Feral

Laconde

Amblard

et al. 2020

Advanced Therapeutics

View full text Add to dashboard Cite

Since the development of the first protein kinase inhibitor in the early 1980s, followed by the FDA approval of imatinib in 2001, kinases are one of the most intensively pursued targets in current medicinal chemistry research. These proteins are overrepresented in various diseases such as cancer, inflammation or autoimmune pathologies and play important roles in their physiopathogenic processes. Despite the development and approval of numerous potent kinase inhibitors, drug resistance and off‐target side effects are commonly encountered with kinase inhibitors. Thus, development of novel strategies to overcome these problems is necessary. Since 2013, many research groups have proposed the conversion of potent kinase inhibitors into PROteolysis TArgeting Chimera (PROTAC) compounds and shared relevant and encouraging results using this new technology, which degrades proteins by employing the cellular machinery. Generally, this strategy brings enhancements in biological effects compared to the use of only the parent inhibitor. In this review article, recent findings related to the PROTAC technology applied to kinases are discussed, with a special focus on publications since 2018.

show abstract

“…A key challenge in PROTAC design to date is the selection of the optimal linker to connect these two binding components. In most cases, linkers of various lengths are screened using synthetically accessible chemistry [15][16][17][18][19] . In some cases, it was shown that a protein-protein interface between the target and the E3 ligase, including interactions with the linker, is important for cooperativity 4 .…”

Section: Introductionmentioning

confidence: 99%

PRosettaC: Rosetta based modeling of PROTAC mediated ternary complexes

Zaidman

London

2020

Preprint

View full text Add to dashboard Cite

Proteolysis-targeting chimeras (PROTACs), which induce degradation by recruitment of an E3 ligase to a target protein, are gaining much interest as a new pharmacological modality. However, designing PROTACs is challenging. Formation of a ternary complex between the protein target, the PROTAC and the recruited E3 ligase is considered paramount for successful degradation. A structural model of this ternary complex could in principle inform rational PROTAC design. Unfortunately, only a handful of structures are available for such complexes, necessitating tools for their modeling. We developed a combined protocol that alternates between sampling of the protein-protein interaction space and the PROTAC molecule conformational space. Application of this protocol -PRosettaC -to a benchmark of known PROTAC ternary complexes results in near-native predictions, with often atomic accuracy prediction of the protein chains, as well as the PROTAC binding moieties. It allowed the modeling of a CRBN/BTK complex that recapitulated experimental results for a series of PROTACs. PRosettaC generated models may be used to design PROTACs for new targets, as well as improve PROTACs for existing targets, potentially cutting down time and synthesis efforts.

show abstract

Solid-phase synthesis for thalidomide-based proteolysis-targeting chimeras (PROTAC)

Abstract: A novel chemical tool for the rapid preparation of PROTAC conjugates by persons without extensive synthetic experience or special laboratory equipment.

Cited by 43 publications

References 23 publications

Sensitive and quantitative detection of MHC-I displayed neoepitopes using a semi-automated workflow and TOMAHAQ mass spectrometry

Sensitive and quantitative detection of MHC-I displayed neoepitopes using a semi-automated workflow and TOMAHAQ mass spectrometry

PROteolysis TArgetting Chimeras (PROTACs) Strategy Applied to Kinases: Recent Advances

PRosettaC: Rosetta based modeling of PROTAC mediated ternary complexes

Contact Info

Product

Resources

About