Expanding the reaction toolbox for nanoscale direct-to-biology PROTAC synthesis and biological evaluation DOI
Rebecca Stevens,

Harry J. Shrives,

Jenni Cryan

et al.

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 16(3), P. 1141 - 1150

Published: Dec. 23, 2024

High-throughput chemistry (HTC) and direct-to-biology (D2B) platforms allow for plate-based compound synthesis biological evaluation of crude mixtures in cellular assays.

Language: Английский

Precision oncology revolution: CRISPR-Cas9 and PROTAC technologies unleashed DOI Creative Commons

Karim Kanbar,

Roy El Darzi,

Diana E. Jaalouk

et al.

Frontiers in Genetics, Journal Year: 2024, Volume and Issue: 15

Published: July 31, 2024

Cancer continues to present a substantial global health challenge, with its incidence and mortality rates persistently reflecting significant impact. The emergence of precision oncology has provided breakthrough in targeting oncogenic drivers previously deemed “undruggable” by conventional therapeutics limiting off-target cytotoxicity. Two groundbreaking technologies that have revolutionized the field are primarily CRISPR-Cas9 gene editing more recently PROTAC (PROteolysis TArgeting Chimeras) targeted protein degradation technology. CRISPR-Cas9, particular, gained widespread recognition acclaim due remarkable ability modify DNA sequences precisely. Rather than genetic code, PROTACs harness ubiquitin proteasome machinery degrade proteins interest selectively. Even though operate on different principles, they share common goal advancing whereby both approaches demonstrated potential preclinical promising data clinical trials. this genes directly indirectly precise, efficient, reversible, adaptable, tissue-specific manner, as diagnostic tool. On other hand, administer low doses orally, broad targeting, tissue specificity, controllability reinforced PROTAC. Thus, oncology, using CRISPR technology interventions, while further expanded therapeutic landscape enabling selective degradation. viewing them mutually exclusive or competing methods their use is context-dependent (i.e., based molecular mechanisms disease) potentially could be used synergistically complementing strengths vice versa . Herein, we review current status designs implications terms potential, trial data, limitations, compare oncology.

Language: Английский

Citations

1
Rapid Affinity and Microsomal Stability Ranking of Crude Mixture Libraries of Histone Deacetylase Inhibitors DOI
Sriram Tyagarajan,

Christine L. Andrews,

Douglas C. Beshore

et al.

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(10), P. 1787 - 1794

Published: Sept. 12, 2024

The science of drug discovery involves multiparameter optimization molecular structures through iterative design-make-test cycles. For medicinal chemistry library synthesis, traditional workflows involve the isolation each individual compound, gravimetric quantitation, and preparation a standard concentration solution for biological assays. In this work, we explore ways to expedite process by testing unpurified mixtures using combination mass spectrometry-based assays affinity selection microsomal metabolic stability. Utilizing approach, microgram quantities crude can be used identify high affinity, metabolically stable members full characterization. This streamlined approach was demonstrated synthesis evaluation two libraries histone deacetylase inhibitors shown generate decision-making data in line with workflows. advantages paradigm include greatly reduced cycle time, material requirements, resources on most promising compounds.

Language: Английский

Citations

1
To homeostasis and beyond! Recent advances in the medicinal chemistry of heterobifunctional derivatives DOI

Diana Castagna,

Benoit Gourdet,

Roland Hjerpe

et al.

Progress in medicinal chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 61 - 160

Published: Jan. 1, 2024

Language: Английский

Citations

1
On-demand modular assembly for expedited PROTAC development DOI Creative Commons
Ayan Mukherjee, Vilas D. Kadam, Qi Miao

et al.

Expert Opinion on Drug Discovery, Journal Year: 2024, Volume and Issue: 19(7), P. 769 - 772

Published: June 6, 2024

KEYWORDS: PROTACclick chemistrylibrary synthesisparallel synthesisdirect-to-biologysplit linkermodular assembly

Language: Английский

Citations

0
Induced degradation of SNAP-fusion proteins DOI

Savina Abraham Pol,

Sara Liljenberg, Jack Barr

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 18, 2024

SUMMARY Self-labeling protein tags are an efficient means to visualize, manipulate, and isolate engineered fusion proteins with suitable chemical probes. The SNAP-tag, which covalently conjugates benzyl-guanine -chloropyrimidine derivatives is used extensively in fluorescence microscopy, given the availability of SNAP-ligand-based Here, we extend applicability SNAP-tag targeted degradation. We developed a set SNAP PROteolysis TArgeting Chimeras (SNAP-PROTACs), recruit VHL or CRBN-ubiquitin E3 ligases induce degradation SNAP-fusion proteins. Endogenous tagging enabled visualization selective depletion SNAP-clathrin light chain using SNAP-PROTACs. addition PROTACs reagent toolbox facilitates comprehensive analysis function single gene event.

Language: Английский

Citations

0
We are MedChem: The Frontiers in Medicinal Chemistry 2024 DOI
Matthias Schiedel,

Philipp Barbie,

Felix Pape

et al.

ChemMedChem, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 23, 2024

The Frontiers in Medicinal Chemistry (FiMC) is the largest international conference Germany and took place from March 17

Language: Английский

Citations

0
Induced degradation of SNAP-fusion proteins DOI Creative Commons

Savina Abraham Pol,

Sara Liljenberg, Jack Barr

et al.

RSC Chemical Biology, Journal Year: 2024, Volume and Issue: 5(12), P. 1232 - 1247

Published: Jan. 1, 2024

Extending the applications of SNAP-tag: VHL- and CRBN-recruiting SNAP-PROTACs provide a ready-to-use targeted protein degradation system for SNAP-fusion proteins.

Language: Английский

Citations

0
Efficient Sampling of PROTAC-Induced Ternary Complexes DOI Creative Commons
Hongtao Zhao, Stefan Schießer, Christian Tyrchan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Abstract Proteolysis targeting chimeras (PROTACs) are bifunctional small molecules that recruit an E3 ligase to a target protein, leading ubiquitin transfer and subsequent proteasomal degradation. The formation of ternary complexes is crucial step in PROTAC-induced protein degradation, gaining structural insights essential for rational PROTAC design. In this study, we present novel approach efficiently sampling complexes, which has been validated using 40 co-crystallized complex structures. comparison protein-protein docking-based integrative approaches, our method achieved impressive success rate 97% 50% retrospectively, measured by C α -RMSD the crystal structure within 10 4 Å, respectively, with average CPU time hours. Notably, utilizing unbound structures, values between predicted experimental structures were consistently 7 Å across six WDR5-PROTAC-VHL Our open-source software enables modeling single holds promise enhancing design efforts. TOC

Language: Английский

Citations

0
Expanding the reaction toolbox for nanoscale direct-to-biology PROTAC synthesis and biological evaluation DOI
Rebecca Stevens,

Harry J. Shrives,

Jenni Cryan

et al.

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 16(3), P. 1141 - 1150

Published: Dec. 23, 2024

High-throughput chemistry (HTC) and direct-to-biology (D2B) platforms allow for plate-based compound synthesis biological evaluation of crude mixtures in cellular assays.

Language: Английский

Citations

0