Identification and Evaluation of Reversible Covalent Binders to Cys55 of Bfl-1 from a DNA-Encoded Chemical Library Screen

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(6), P. 791 - 797

Published: May 20, 2024

Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of are highly desirable. A DNA-encoded chemical library (DEL) screen against identified the first known reversible covalent small-molecule ligand for Bfl-1. The binding was validated through biophysical biochemical techniques, which confirmed mechanism action pointed to Cys55. This represented identification a cyano-acrylamide compound from DEL highlights further opportunities drug discovery screening. 10-fold improvement potency achieved systematic SAR exploration hit. more potent analogue

Language: Английский

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Discovery of a Series of Covalent Ligands That Bind to Cys77 of the Von Hippel–Lindau Tumor Suppressor Protein (VHL)

ACS Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: 16(4), P. 693 - 699

Published: March 19, 2025

Most ligands for the Von Hippel-Lindau tumor suppressor (VHL) bind at HIF-1α binding site. Ligands that to allosteric sites on VHL could be highly valuable field of protein degradation, therefore, a covalent hit identification campaign was run targeting Cys77 VHL. Hit 2 bound selectively and did not alkylate reactive Cys89 Elongin B. It showed time- concentration-dependent labeling, with k inact/K I 0.30 M-1 s-1, does affect This ligand optimized afford compound 15 which improved potency labeling An X-ray structure close analogue determined revealing in shallow groove surface These are first small molecules covalently an site provide suitable starting point further optimization.

Language: Английский

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Go for Gold: Development of a Scalable Synthesis of [1‐(Ethoxycarbonyl)cyclopropyl] Triphenylphosphonium Tetrafluoroborate, a Key Reagent to Explore Covalent Monopolar Spindle 1 Inhibitors

ChemistryOpen, Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

Covalent approaches have resurged in drug discovery and chemical biology during the last decade. So‐called targeted covalent inhibitors typically show a strong persistent drug–target interaction as well high degree of selectivity. In our research group, RMS‐07 (8) , First‐in‐Class inhibitor protein kinase threonine tyrosine (TTK)/monopolar spindle 1, which shows promising results variety different solid cancer cell types will be further optimized terms binding kinetics, has recently been developed. However, synthetic accessibility is restricted by price limited availability [1‐(ethoxycarbonyl)cyclopropyl] triphenylphosphonium tetrafluoroborate ( 10 ), key reagent required to assemble tricyclic core scaffold Wittig‐type cyclization reaction. This also described valuable synthon for synthesis range ring systems with interesting applications medicinal chemistry. reliable procedures its large‐scale are scarce. Only one prior report describes it contains experimental details, making challenging reproduce scale up. Herein, concise reproducible decigram‐scale protocol accessing described.

Language: Английский

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Design of a Lead-Like Cysteine-Targeting Covalent Library and the Identification of Hits to Cys55 of Bfl-1

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(13), P. 11209 - 11225

Published: June 25, 2024

Covalent hit identification is a viable approach to identify chemical starting points against difficult-to-drug targets. While most researchers screen libraries of <2k electrophilic fragments, focusing on lead-like compounds can be advantageous in terms finding hits with improved affinity and better chance identifying cryptic pockets. However, due the increased molecular complexity, larger numbers (>10k) are desirable ensure adequate coverage space. Herein, taken build library 12k covalent reported, utilizing legacy compounds, robust chemistry, acquisitions. The was screened antiapoptotic protein Bfl-1, six promising that displaced BIM peptide from PPI interface were identified. Intriguingly, X-ray crystallography compound

Language: Английский

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Hit me with your best shot: Integrated hit discovery for the next generation of drug targets

Drug Discovery Today, Journal Year: 2024, Volume and Issue: 29(10), P. 104143 - 104143

Published: Aug. 23, 2024

Language: Английский

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Accelerating Covalent Binding Studies: Direct mass shift measurement with acoustic ejection and TOF-MS

SLAS TECHNOLOGY, Journal Year: 2024, Volume and Issue: unknown, P. 100216 - 100216

Published: Oct. 1, 2024

Tracking chemical reactions by measuring incurred mass shifts upon successful binding is a direct and attractive alternative to existing assays based on tags. Traditional methods use liquid chromatography-mass spectrometry (LC-MS), because the required buffers are not amenable MS injection, sample pre-treatment needed desalt. This leads analysis times from ten seconds minutes per sample, limiting throughput preventing widespread application. Combining an acoustic ejection (AE) interface with time-of-flight spectrometer (MS) removes this bottleneck, as samples can be directly introduced at rates of up one second sample. article describes complete workflow for covalent compounds proteins in real-time, assay data evaluation. It noteworthy that first instance using SCIEX Echo® MS+ system ZenoTOF 7600 study kinetic regimes binding.

Language: Английский

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Innovative design and potential applications of covalent strategy in drug discovery

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 284, P. 117202 - 117202

Published: Dec. 26, 2024

Language: Английский

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