Aurora A regulation by reversible cysteine oxidation reveals evolutionarily conserved redox control of Ser/Thr protein kinase activity

Science Signaling, Journal Year: 2020, Volume and Issue: 13(639)

Published: July 7, 2020

Reactive oxygen species (ROS) are physiological mediators of cellular signaling and play potentially damaging roles in human diseases. In this study, we found that the catalytic activity Ser/Thr kinase Aurora A was inhibited by oxidation a conserved cysteine residue (Cys

Language: Английский

---

Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells

Science Signaling, Journal Year: 2018, Volume and Issue: 11(549)

Published: Sept. 25, 2018

Covalent EGFR family inhibitors bind to and induce the degradation of pseudokinase TRIB2 kill cancer cells.

Language: Английский

---

Site-Specific Labeling of Endogenous Proteins Using CoLDR Chemistry

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(48), P. 20095 - 20108

Published: Nov. 24, 2021

Chemical modifications of native proteins can affect their stability, activity, interactions, localization, and more. However, there are few nongenetic methods for the installation chemical at a specific protein site in cells. Here we report covalent ligand directed release (CoLDR) site-specific labeling strategy, which enables variety functional tags on target while releasing directing ligand. Using this approach, were able to label various such as BTK, K-RasG12C, SARS-CoV-2 PLpro with different tags. For BTK have shown selective cells both alkyne fluorophores Protein by traditional affinity often inhibits activity since permanently occupies binding pocket. We that using CoLDR chemistry, modification these probes preserves its activity. demonstrated several applications approach including determining half-life environment minimal perturbation, well quantification degradation noncovalent proteolysis targeting chimera (PROTAC) in-gel fluorescence. an environment-sensitive "turn-on" fluorescent probe, monitor active BTK. Finally, efficient CoLDR-based PROTACs (DC50 < 100 nM), installed CRBN binder onto This joins very available strategies maintain thus makes important addition toolbox biology.

Language: Английский

---

Strategic Design of Catalytic Lysine‐Targeting Reversible Covalent BCR‐ABL Inhibitors**

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 60(31), P. 17131 - 17137

Published: May 19, 2021

Abstract Targeted covalent inhibitors have re‐emerged as validated drugs to overcome acquired resistance in cancer treatment. Herein, by using a carbonyl boronic acid (CBA) warhead, we report the structure‐based design of BCR‐ABL via reversible targeting catalytic lysine with improved potency against both wild‐type and mutant ABL kinases, especially T315I bearing gatekeeper residue mutation. We show evolutionarily conserved can be targeted selectively, selectivity depends largely on molecular recognition non‐covalent pharmacophore this class inhibitors, probably due moderate reactivity warhead. first co‐crystal structures inhibitor‐ABL kinase domain complexes, providing insights into interaction warhead lysine. also employed label‐free mass spectrometry evaluate off‐targets our compounds at proteome‐wide level different mammalian cells.

Language: Английский

---

PROTAC degraders as chemical probes for studying target biology and target validation

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(18), P. 7971 - 7993

Published: Jan. 1, 2022

This review provides guidelines for the optimization of proteolysis targeting chimeras (PROTACs) and outlines criteria their use as chemical probes.

Language: Английский

---